Murakami Masaaki
| Institute for Genetic Medicine Molecular Pathogenesis | Professor |
| Institute for Integrated Innovations | Professor |
| Institute for Integrated Innovations Institute for Vaccine Research and Development | Professor |
Last Updated :2025/06/07
■Researcher basic information
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J-Global ID
Research Keyword
Educational Organization
- Master's degree program, Graduate School of Medicine
- Doctoral (PhD) degree program, Graduate School of Medicine
■Career
Career
Educational Background
Position History
- 遺伝子病制御研究所長, 2016年4月1日 - 2018年3月31日
- 遺伝子病制御研究所長, 2018年4月1日 - 2020年3月31日
- 遺伝子病制御研究所長, 2022年4月1日 - 2024年3月31日
- 遺伝子病制御研究所長, 2024年4月1日 - 2026年3月31日
- 遺伝子病制御研究所附属感染癌研究センター長, 2020年4月1日 - 2022年3月31日
- 遺伝子病制御研究所副所長, 2020年4月1日 - 2022年3月31日
- 教育研究評議会評議員, 2016年4月1日 - 2018年3月31日
- 教育研究評議会評議員, 2018年4月1日 - 2020年3月31日
- 教育研究評議会評議員, 2022年4月1日 - 2024年3月31日
■Research activity information
Papers
- MitoNEET reduces the mitochondrial oxidative phosphorylation during epithelial-mesenchymal transition
Haruka Handa, Yasuhito Onodera, Tsukasa Oikawa, Shingo Takada, Koji Ueda, Daiki Setoyama, Takashi Yokota, Miwako Yamasaki, Masahiko Watanabe, Yoshizuki Fumoto, Ari Hashimoto, Soichiro Hata, Masaaki Murakami, Hisataka Sabe
Cold Spring Harbor Laboratory, 29 Jul. 2024
Mitochondrial functions range from catabolic to anabolic, which are tightly coordinated to meet cellular demands for proliferation and motility. MitoNEET is a mitochondrial outer membrane protein with a CDGSH domain and is involved in mitochondrial function. Epithelial-to-mesenchymal transition (EMT) is the process in which cells lose their epithelial characteristics and acquire mesenchymal traits, such as motility, which is a vital step for organism development and wound-healing. Cellular motility is associated with high ATP consumption owing to lamellipodia formation, which is supported by upregulated oxidative phosphorylation (OXPHOS) capacity. However, how mitoNEET is involved in the regulation of OXPHOS capacity and subsequent cellular motility remains unclear. Here we show that loss of mitoNEET regulation during EMT impairs both OXPHOS enhancement and cell motility in non-transformed NMuMG mouse mammary gland epithelial cells. We found that mitoNEET is downregulated during EMT, and that the aberrant expression of mitoNEET abolishes the upregulation of OXPHOS, leading to the inhibition of cell motility. Furthermore, we found that mitoNEET topology may be crucial for the regulation of the mitochondrial electron transfer chain, suggesting an additional regulatory pathway for OXPHOS capacity. Our results demonstrate that mitochondrial OXPHOS capacity during EMT is partly regulated by the dynamics of the outer membrane protein. We believe that our findings are the first step towards understanding the mechanisms by which mitochondrial outer membrane protein topology affects organelle functions - GGT1 is a SNP eQTL gene involved in STAT3 activation and associated with the development of Post-ERCP pancreatitis.
Ryutaro Furukawa, Masaki Kuwatani, Jing-Jing Jiang, Yuki Tanaka, Rie Hasebe, Kaoru Murakami, Kumiko Tanaka, Noriyuki Hirata, Izuru Ohki, Ikuko Takahashi, Takeshi Yamasaki, Yuta Shinohara, Shunichiro Nozawa, Shintaro Hojyo, Shimpei I Kubota, Shigeru Hashimoto, Satoshi Hirano, Naoya Sakamoto, Masaaki Murakami
Scientific reports, 14, 1, 12224, 12224, 28 May 2024, [International Magazine]
English, Scientific journal, Post-ERCP pancreatitis (PEP) is an acute pancreatitis caused by endoscopic-retrograde-cholangiopancreatography (ERCP). About 10% of patients develop PEP after ERCP. Here we show that gamma-glutamyltransferase 1 (GGT1)-SNP rs5751901 is an eQTL in pancreatic cells associated with PEP and a positive regulator of the IL-6 amplifier. More PEP patients had the GGT1 SNP rs5751901 risk allele (C) than that of non-PEP patients at Hokkaido University Hospital. Additionally, GGT1 expression and IL-6 amplifier activation were increased in PEP pancreas samples with the risk allele. A mechanistic analysis showed that IL-6-mediated STAT3 nuclear translocation and STAT3 phosphorylation were suppressed in GGT1-deficient cells. Furthermore, GGT1 directly associated with gp130, the signal-transducer of IL-6. Importantly, GGT1-deficiency suppressed inflammation development in a STAT3/NF-κB-dependent disease model. Thus, the risk allele of GGT1-SNP rs5751901 is involved in the pathogenesis of PEP via IL-6 amplifier activation. Therefore, the GGT1-STAT3 axis in pancreas may be a prognosis marker and therapeutic target for PEP. - DDX6 is involved in the pathogenesis of inflammatory diseases via NF-κB activation
Seiichiro Naito, Hiroki Tanaka, Jing-Jing Jiang, Masato Tarumi, Ari Hashimoto, Yuki Tanaka, Kaoru Murakami, Shimpei I. Kubota, Shintaro Hojyo, Shigeru Hashimoto, Masaaki Murakami
Biochemical and Biophysical Research Communications, 703, 149666, 149666, Elsevier BV, Apr. 2024
Scientific journal - The gateway reflex regulates tissue-specific autoimmune diseases.
Yuki Tanaka, Izuru Ohki, Kaoru Murakami, Satoshi Ozawa, Yaze Wang, Masaaki Murakami
Inflammation and regeneration, 44, 1, 12, 12, 07 Mar. 2024, [International Magazine]
English, Scientific journal, The dynamic interaction and movement of substances and cells between the central nervous system (CNS) and peripheral organs are meticulously controlled by a specialized vascular structure, the blood-brain barrier (BBB). Experimental and clinical research has shown that disruptions in the BBB are characteristic of various neuroinflammatory disorders, including multiple sclerosis. We have been elucidating a mechanism termed the "gateway reflex" that details the entry of immune cells, notably autoreactive T cells, into the CNS at the onset of such diseases. This process is initiated through local neural responses to a range of environmental stimuli, such as gravity, electricity, pain, stress, light, and joint inflammation. These stimuli specifically activate neural pathways to open gateways at targeted blood vessels for blood immune cell entry. The gateway reflex is pivotal in managing tissue-specific inflammatory diseases, and its improper activation is linked to disease progression. In this review, we present a comprehensive examination of the gateway reflex mechanism. - Gateway reflexes describe novel neuro-immune communications that establish immune cell gateways at specific vessels.
Hiroki Tanaka, Rie Hasebe, Kaoru Murakami, Toshiki Sugawara, Takeshi Yamasaki, Masaaki Murakami
Bioelectronic medicine, 9, 1, 24, 24, 08 Nov. 2023, [International Magazine]
English, Scientific journal, Neuroinflammation is an important biological process induced by complex interactions between immune cells and neuronal cells in the central nervous system (CNS). Recent research on the bidirectional communication between neuronal and immunological systems has provided evidence for how immune and inflammatory processes are regulated by nerve activation. One example is the gateway reflex, in which immune cells bypass the blood brain barrier and infiltrate the CNS to cause neuroinflammation. We have found several modes of the gateway reflex in mouse models, in which gateways for immune cells are established at specific blood vessels in the spinal cords and brain in experimental autoimmune encephalomyelitis and systemic lupus erythematosus models, at retinal blood vessels in an experimental autoimmune uveitis model, and the ankle joints in an inflammatory arthritis model. Several environmental stimulations, including physical and psychological stresses, activate neurological pathways that alter immunological responses via the gateway reflex, thus contributing to the development/suppression of autoimmune diseases. In the manuscript, we describe the discovery of the gateway reflex and recent insights on how they regulate disease development. We hypothesize that artificial manipulation of specific neural pathways can establish and/or close the gateways to control the development of autoimmune diseases. - High-precision rapid testing of omicron SARS-CoV-2 variants in clinical samples using AI-nanopore.
Kaoru Murakami, Shimpei I Kubota, Kumiko Tanaka, Hiroki Tanaka, Keiichiroh Akabane, Rigel Suzuki, Yuta Shinohara, Hiroyasu Takei, Shigeru Hashimoto, Yuki Tanaka, Shintaro Hojyo, Osamu Sakamoto, Norihiko Naono, Takayui Takaai, Kazuki Sato, Yuichi Kojima, Toshiyuki Harada, Takeshi Hattori, Satoshi Fuke, Isao Yokota, Satoshi Konno, Takashi Washio, Takasuke Fukuhara, Takanori Teshima, Masateru Taniguchi, Masaaki Murakami
Lab on a chip, 23, 22, 4909, 4918, 07 Nov. 2023, [International Magazine]
English, Scientific journal, A digital platform that can rapidly and accurately diagnose pathogenic viral variants, including SARS-CoV-2, will minimize pandemics, public anxiety, and economic losses. We recently reported an artificial intelligence (AI)-nanopore platform that enables testing for Wuhan SARS-CoV-2 with high sensitivity and specificity within five minutes. However, which parts of the virus are recognized by the platform are unknown. Similarly, whether the platform can detect SARS-CoV-2 variants or the presence of the virus in clinical samples needs further study. Here, we demonstrated the platform can distinguish SARS-CoV-2 variants. Further, it identified mutated Wuhan SARS-CoV-2 expressing spike proteins of the delta and omicron variants, indicating it discriminates spike proteins. Finally, we used the platform to identify omicron variants with a sensitivity and specificity of 100% and 94%, respectively, in saliva specimens from COVID-19 patients. Thus, our results demonstrate the AI-nanopore platform is an effective diagnostic tool for SARS-CoV-2 variants. - Dengue virus infection induces selective expansion of Vγ4 and Vγ6TCR γδ T cells in the small intestine and a cytokine storm driving vascular leakage in mice.
Takeshi Kurosu, Daisuke Okuzaki, Yusuke Sakai, Mohamad Al Kadi, Supranee Phanthanawiboon, Yasusi Ami, Masayuki Shimojima, Tomoki Yoshikawa, Shuetsu Fukushi, Noriyo Nagata, Tadaki Suzuki, Daisuke Kamimura, Masaaki Murakami, Hideki Ebihara, Masayuki Saijo
PLoS neglected tropical diseases, 17, 11, e0011743, 08 Nov. 2023, [International Magazine]
English, Scientific journal, Dengue is a major health problem in tropical and subtropical regions. Some patients develop a severe form of dengue, called dengue hemorrhagic fever, which can be fatal. Severe dengue is associated with a transient increase in vascular permeability. A cytokine storm is thought to be the cause of the vascular leakage. Although there are various research reports on the pathogenic mechanism, the complete pathological process remains poorly understood. We previously reported that dengue virus (DENV) type 3 P12/08 strain caused a lethal systemic infection and severe vascular leakage in interferon (IFN)-α/β and γ receptor knockout mice (IFN-α/β/γRKO mice), and that blockade of TNF-α signaling protected mice. Here, we performed transcriptome analysis of liver and small intestine samples collected chronologically from P12/08-infected IFN-α/β/γRKO mice in the presence/absence of blockade of TNF-α signaling and evaluated the cytokine and effector-level events. Blockade of TNF-α signaling mainly protected the small intestine but not the liver. Infection induced the selective expansion of IL-17A-producing Vγ4 and Vγ6 T cell receptor (TCR) γδ T cells in the small intestine, and IL-17A, together with TNF-α, played a critical role in the transition to severe disease via the induction of inflammatory cytokines such as TNF-α, IL-1β, and particularly the excess production of IL-6. Infection also induced the infiltration of neutrophils, as well as neutrophil collagenase/matrix metalloprotease 8 production. Blockade of IL-17A signaling reduced mortality and suppressed the expression of most of these cytokines, including TNF-α, indicating that IL-17A and TNF-α synergistically enhance cytokine expression. Blockade of IL-17A prevented nuclear translocation of NF-κB p65 in stroma-like cells and epithelial cells in the small intestine but only partially prevented recruitment of immune cells to the small intestine. This study provides an overall picture of the pathogenesis of infection in individual mice at the cytokine and effector levels. - Computer model of IL-6-dependent rheumatoid arthritis in F759 mice.
Reiji Yamamoto, Satoshi Yamada, Toru Atsumi, Kaoru Murakami, Ari Hashimoto, Seiichiro Naito, Yuki Tanaka, Izuru Ohki, Yuta Shinohara, Norimasa Iwasaki, Akihiko Yoshimura, Jing-Jing Jiang, Daisuke Kamimura, Shintaro Hojyo, Shimpei I Kubota, Shigeru Hashimoto, Masaaki Murakami
International immunology, 35, 9, 403, 421, Oxford University Press (OUP), 05 Sep. 2023, [International Magazine]
English, Scientific journal, Abstract
The interleukin-6 (IL-6) amplifier, which describes the simultaneous activation of signal transducer and activator of transcription 3 (STAT3) and NF-κb nuclear factor kappa B (NF-κB), in synovial fibroblasts causes the infiltration of immune cells into the joints of F759 mice. The result is a disease that resembles human rheumatoid arthritis. However, the kinetics and regulatory mechanisms of how augmented transcriptional activation by STAT3 and NF-κB leads to F759 arthritis is unknown. We here show that the STAT3-NF-κB complex is present in the cytoplasm and nucleus and accumulates around NF-κB binding sites of the IL-6 promoter region and established a computer model that shows IL-6 and IL-17 (interleukin 17) signaling promotes the formation of the STAT3-NF-κB complex followed by its binding on promoter regions of NF-κB target genes to accelerate inflammatory responses, including the production of IL-6, epiregulin, and C-C motif chemokine ligand 2 (CCL2), phenotypes consistent with in vitro experiments. The binding also promoted cell growth in the synovium and the recruitment of T helper 17 (Th17) cells and macrophages in the joints. Anti-IL-6 blocking antibody treatment inhibited inflammatory responses even at the late phase, but anti-IL-17 and anti-TNFα antibodies did not. However, anti-IL-17 antibody at the early phase showed inhibitory effects, suggesting that the IL-6 amplifier is dependent on IL-6 and IL-17 stimulation at the early phase, but only on IL-6 at the late phase. These findings demonstrate the molecular mechanism of F759 arthritis can be recapitulated in silico and identify a possible therapeutic strategy for IL-6 amplifier-dependent chronic inflammatory diseases. - ウエストナイルウイルスの脳内侵入機構解明のための脳組織の病理組織学的解析
梶山 実紗, 福田 幸音, 佐々木 道仁, Passawat Thammahkin, 前園 佳祐, 長谷部 理絵, 村上 正晃, 苅和 宏明, 小林 進太郎
日本獣医学会学術集会講演要旨集, 166回, 150, 150, (公社)日本獣医学会, Sep. 2023
Japanese - An inflammatory bowel disease-associated SNP increases local thyroglobulin expression to develop inflammation in miniature dachshunds
Yong Bin Teoh, Jing-Jing Jiang, Takeshi Yamasaki, Noriyuki Nagata, Toshiki Sugawara, Rie Hasebe, Hiroshi Ohta, Noboru Sasaki, Nozomu Yokoyama, Kensuke Nakamura, Yumiko Kagawa, Mitsuyoshi Takiguchi, Masaaki Murakami
Frontiers in Veterinary Science, 10, Frontiers Media SA, 14 Jul. 2023
Scientific journal, Inflammatory colorectal polyp (ICRP) in miniature dachshunds (MDs) is a chronic inflammatory bowel disease (IBD) characterized by granulomatous inflammation that consists of neutrophil infiltration and goblet cell hyperplasia in the colon. Recently, we identified five MD-associated single-nucleotide polymorphisms (SNPs), namely PLG, TCOF1, TG, COL9A2, and COL4A4, by whole-exome sequencing. Here, we investigated whether TG c.4567C>T (p.R1523W) is associated with the ICRP pathology. We found that the frequency of the T/T SNP risk allele was significantly increased in MDs with ICRP. In vitro experiments showed that TG expression in non-immune cells was increased by inducing the IL-6 amplifier with IL-6 and TNF-α. On the other hand, a deficiency of TG suppressed the IL-6 amplifier. Moreover, recombinant TG treatment enhanced the activation of the IL-6 amplifier, suggesting that TG is both a positive regulator and a target of the IL-6 amplifier. We also found that TG expression together with two NF-κB targets, IL6 and CCL2, was increased in colon samples isolated from MDs with the T/T risk allele compared to those with the C/C non-risk allele, but serum TG was not increased. Cumulatively, these results suggest that the T/T SNP is an expression quantitative trait locus (eQTL) of TG mRNA in the colon, and local TG expression triggered by this SNP increases the risk of ICRP in MDs via the IL-6 amplifier. Therefore, TG c.4567C>T is a diagnostic target for ICRP in MDs, and TG-mediated IL-6 amplifier activation in the colon is a possible therapeutic target for ICRP. - GM-CSF Promotes the Survival of Peripheral-Derived Myeloid Cells in the Central Nervous System for Pain-Induced Relapse of Neuroinflammation.
Shiina Matsuyama, Reiji Yamamoto, Kaoru Murakami, Nobuhiko Takahashi, Rieko Nishi, Asuka Ishii, Junko Nio-Kobayashi, Nobuya Abe, Kumiko Tanaka, Jing-Jing Jiang, Tadafumi Kawamoto, Toshihiko Iwanaga, Yuta Shinohara, Takeshi Yamasaki, Izuru Ohki, Shintaro Hojyo, Rie Hasebe, Shimpei I Kubota, Noriyuki Hirata, Daisuke Kamimura, Shigeru Hashimoto, Yuki Tanaka, Masaaki Murakami
Journal of immunology (Baltimore, Md. : 1950), 211, 1, 34, 42, 01 Jul. 2023, [International Magazine]
English, Scientific journal, We recently discovered a (to our knowledge) new neuroimmune interaction named the gateway reflex, in which the activation of specific neural circuits establishes immune cell gateways at specific vessel sites in organs, leading to the development of tissue-specific autoimmune diseases, including a multiple sclerosis (MS) mouse model, experimental autoimmune encephalomyelitis (EAE). We have reported that peripheral-derived myeloid cells, which are CD11b+MHC class II+ and accumulate in the fifth lumbar (L5) cord during the onset of a transfer model of EAE (tEAE), play a role in the pain-mediated relapse via the pain-gateway reflex. In this study, we investigated how these cells survive during the remission phase to cause the relapse. We show that peripheral-derived myeloid cells accumulated in the L5 cord after tEAE induction and survive more than other immune cells. These myeloid cells, which highly expressed GM-CSFRα with common β chain molecules, grew in number and expressed more Bcl-xL after GM-CSF treatment but decreased in number by blockade of the GM-CSF pathway, which suppressed pain-mediated relapse of neuroinflammation. Therefore, GM-CSF is a survival factor for these cells. Moreover, these cells were colocalized with blood endothelial cells (BECs) around the L5 cord, and BECs expressed a high level of GM-CSF. Thus, GM-CSF from BECs may have an important role in the pain-mediated tEAE relapse caused by peripheral-derived myeloid cells in the CNS. Finally, we found that blockade of the GM-CSF pathway after pain induction suppressed EAE development. Therefore, GM-CSF suppression is a possible therapeutic approach in inflammatory CNS diseases with relapse, such as MS. - Calcineurin inhibitor inhibits tolerance induction by suppressing terminal exhaustion of donor T cells after allo-HCT.
Hajime Senjo, Shinpei Harada, Shimpei I Kubota, Yuki Tanaka, Takahiro Tateno, Zixuan Zhang, Satomi Okada, Xuanzhong Chen, Ryo Kikuchi, Naoki Miyashita, Masahiro Onozawa, Hideki Goto, Tomoyuki Endo, Yuta Hasegawa, Hiroyuki Ohigashi, Takahide Ara, Yoshinori Hasegawa, Masaaki Murakami, Takanori Teshima, Daigo Hashimoto
Blood, 22 May 2023, [International Magazine]
English, Scientific journal, Calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis is standard in allogeneic hematopoietic stem cell transplantation (HCT) but fails to induce long-term tolerance without chronic GVHD in a considerable number of patients. In this study, we addressed this long-standing question in mouse models of HCT. After HCT, alloreactive donor T cells rapidly differentiated into PD-1+ TIGIT+ terminally exhausted T cells (terminal-Tex). GVHD prophylaxis with cyclosporine (CSP) suppressed donor T-cell expression of TOX, a master regulator to promote differentiation of transitory exhausted T cells (transitory-Tex), expressing both inhibitory receptors and effector molecules, into terminal-Tex, and inhibited tolerance induction. Adoptive transfer of transitory-Tex, but not terminal-Tex, into secondary recipients developed chronic GVHD. Transitory-Tex maintained alloreactivity and thus PD-1 blockade restored graft-versus-leukemia (GVL) activity of transitory-Tex, not terminal-Tex. In conclusion, CSP inhibits tolerance induction by suppressing the terminal exhaustion of donor T cells, while maintaining GVL effects to suppress leukemia relapse. - In situ Microinflammation Detection Using Gold Nanoclusters and a Tissue-clearing Method.
Fayrouz Naim, Rie Hasebe, Shintaro Hojyo, Yukatsu Shichibu, Asuka Ishii, Yuki Tanaka, Kazuki Tainaka, Shimpei I Kubota, Katsuaki Konishi, Masaaki Murakami
Bio-protocol, 13, 7, e4644, 05 Apr. 2023, [International Magazine]
English, Scientific journal, Microinflammation enhances the permeability of specific blood vessel sites through an elevation of local inflammatory mediators, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α. By a two-dimensional immunohistochemistry analysis of tissue sections from mice with experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS), we previously showed that pathogenic immune cells, including CD4+ T cells, specifically accumulate and cause microinflammation at the dorsal vessels of the fifth lumbar cord (L5), resulting in the onset of disease. However, usual pathological analyses by using immunohistochemistry on sections are not effective at identifying the microinflammation sites in organs. Here, we developed a new three-dimensional visualization method of microinflammation using luminescent gold nanoclusters (AuNCs) and the clear, unobstructed brain/body imaging cocktails and computational analysis (CUBIC) tissue-clearing method. Our protocol is based on the detection of leaked AuNCs from the blood vessels due to an enhanced vascular permeability caused by the microinflammation. When we injected ultrasmall coordinated Au13 nanoclusters intravenously (i.v.) to EAE mice, and then subjected the spinal cords to tissue clearing, we detected Au signals leaked from the blood vessels at L5 by light sheet microscopy, which enabled the visualization of complex tissue structures at the whole organ level, consistent with our previous report that microinflammation occurs specifically at this site. Our method will be useful to specify and track the stepwise development of microinflammation in whole organs that is triggered by the recruitment of pathogenic immune cells at specific blood vessels in various inflammatory diseases. - Combination therapy with bevacizumab and a CCR2 inhibitor for human ovarian cancer: An in vivo validation study.
Tianyue Zhai, Takashi Mitamura, Lei Wang, Shimpei I Kubota, Masaaki Murakami, Shinya Tanaka, Hidemichi Watari
Cancer medicine, 12, 8, 9697, 9708, Apr. 2023, [International Magazine]
English, Scientific journal, BACKGROUND: Anti-angiogenic therapy with bevacizumab (BEV), an anti-VEGF antibody, plays a critical role in the treatment of ovarian cancer. However, despite an encouraging initial response, most tumors become resistant to BEV over time, and a new strategy that enables sustainable treatment using BEV is therefore needed. METHODS: To overcome the resistance to BEV in patients with ovarian cancer, we performed a validation study of combination therapy with BEV (10 mg/kg) and the CCR2 inhibitor BMS CCR2 22 (20 mg/kg) (BEV/CCR2i) using 3 consecutive patient-derived xenografts (PDXs) of immunodeficient mice. RESULTS: BEV/CCR2i demonstrated a significant effect of growth suppression in the BEV-resistant serous PDX and BEV-sensitive serous PDX compared with BEV (30.4% after the second cycle and 15.5% after the first cycle, respectively), and treatment cessation did not attenuate this effect. Tissue clearing and immunohistochemistry with an anti-α-SMA antibody suggested that BEV/CCR2i suppressed angiogenesis from the host mice more than BEV. In addition, human CD31 immunohistochemistry revealed that BEV/CCR2i decreased microvessels originating from the patients to a significantly greater degree than BEV. Regarding the BEV-resistant clear cell PDX, the effect of BEV/CCR2i was unclear during the first five cycles, but the following two cycles of increased-dose BEV/CCR2i (CCR2i 40 mg/kg) significantly suppressed tumor growth compared with BEV (28.3%) by inhibiting the CCR2B-MAPK pathway. CONCLUSIONS: BEV/CCR2i showed a sustained anticancer immunity-independent effect in human ovarian cancer that was more significant in serous carcinoma than in clear cell carcinoma. - Zoobiquity experiments show the importance of the local MMP9-plasminogen axis in inflammatory bowel diseases in both dogs and patients.
Takeshi Yamasaki, Noriyuki Nagata, Toru Atsumi, Rie Hasebe, Yuki Tanaka, Izuru Ohki, Shimpei Kubota, Yuta Shinohara, Yong Bin Teoh, Nozomu Yokoyama, Noboru Sasaki, Kensuke Nakamura, Hiroshi Ohta, Takehiko Katsurada, Yoshihiro Matsuno, Shintaro Hojyo, Shigeru Hashimoto, Mitsuyoshi Takiguchi, Masaaki Murakami
International immunology, 35, 7, 313, 326, 18 Mar. 2023, [International Magazine]
English, Scientific journal, Using a zoobiquity concept, we directly connect animal phenotypes to a human disease mechanism: the reduction of local plasminogen levels caused by matrix metalloproteinase-9 (MMP9) activity is associated with the development of inflammation in the intestines of dogs and patients with inflammatory bowel disease. We first investigated inflammatory colorectal polyps (ICRPs), which are a canine gastrointestinal disease characterized by the presence of idiopathic chronic inflammation, in Miniature Dachshund (MD), and found 31 missense disease-associated SNPs by whole-exome sequencing. We sequenced them in 10 other dog breeds and found five, PLG, TCOF1, TG, COL9A2, and COL4A4, only in MD. We then investigated two rare and breed-specific missense SNPs (T/T SNPs), PLG: c.477G>T and c.478A>T, and found that ICRPs with the T/T SNP risk-alleles showed less intact plasminogen and plasmin activity in the lesions compared to ICRPs without the risk-alleles but no differences in serum. Moreover, we show that MMP9, which is a NF-κB target, caused the plasminogen reduction and that intestinal epithelial cells expressing plasminogen molecules were colocalized with epithelial cells expressing MMP9 in normal colons with the risk-alleles. Importantly, MMP9 expression in patients with ulcerous colitis or Crohn's disease also colocalized with epithelial cells showing enhanced NF-κB activation and less plasminogen expression. Overall, our zoobiquity experiments showed that MMP9 induces the plasminogen reduction in intestine, contributing to the development of local inflammation and suggesting the local MMP9-plasminogen axis is a therapeutic target in both dogs and patients. Therefore, zoobiquity-type experiments could bring new perspectives for biomarkers and therapeutic targets. - Antibody feedback contributes to facilitating the development of Omicron-reactive memory B cells in SARS-CoV-2 mRNA vaccinees
Takeshi Inoue, Ryo Shinnakasu, Chie Kawai, Hiromi Yamamoto, Shuhei Sakakibara, Chikako Ono, Yumi Itoh, Tommy Terooatea, Kazuo Yamashita, Toru Okamoto, Noritaka Hashii, Akiko Ishii-Watabe, Noah S. Butler, Yoshiharu Matsuura, Hisatake Matsumoto, Shinya Otsuka, Kei Hiraoka, Takanori Teshima, Masaaki Murakami, Tomohiro Kurosaki
Journal of Experimental Medicine, 220, 2, Rockefeller University Press, 06 Feb. 2023
Scientific journal, In contrast to a second dose of the SARS-CoV-2 mRNA vaccine, a third dose elicits potent neutralizing activity against the Omicron variant. To address the underlying mechanism for this differential antibody response, we examined spike receptor-binding domain (RBD)–specific memory B cells in vaccinated individuals. Frequency of Omicron-reactive memory B cells increased ∼9 mo after the second vaccine dose. These memory B cells show an altered distribution of epitopes from pre-second memory B cells, presumably due to an antibody feedback mechanism. This hypothesis was tested using mouse models, showing that an addition or a depletion of RBD-induced serum antibodies results in a concomitant increase or decrease, respectively, of Omicron-reactive germinal center (GC) and memory B cells. Our data suggest that pre-generated antibodies modulate the selection of GC and subsequent memory B cells after the second vaccine dose, accumulating more Omicron-reactive memory B cells over time, which contributes to the generation of Omicron-neutralizing antibodies elicited by the third vaccine dose. - Dupuytren's contracture-associated SNPs increase SFRP4 expression in nonimmune cells including fibroblasts to enhance inflammation development.
Hiroaki Kida, Jing-Jing Jiang, Yuichiro Matsui, Ikuko Takahashi, Rie Hasebe, Daisuke Kawamura, Takeshi Endo, Hiroki Shibayama, Makoto Kondoh, Yasuhiko Nishio, Kinya Nishida, Yoshihiro Matsuno, Tsukasa Oikawa, Shimpei Kubota, Shintaro Hojyo, Norimasa Iwasaki, Shigeru Hashimoto, Yuki Tanaka, Masaaki Murakami
International immunology, 35, 7, 303, 312, 31 Jan. 2023, [International Magazine]
English, Scientific journal, Dupuytren's contracture (DC) is an inflammatory fibrosis characterized by fibroproliferative disorders of the palmar aponeurosis, for which there is no effective treatment. Although several genome-wide association studies have identified risk alleles associated with DC, the functional linkage between these alleles and the pathogenesis remains elusive. We here focused on two SNPs associated with DC, rs16879765 and rs17171229, in secreted frizzled related protein 4 (SFRP4). We investigated the association of SRFP4 with the IL-6 amplifier, which amplifies the production of IL-6, growth factors, and chemokines in non-immune cells and aggravates inflammatory diseases via NF-κB enhancement. Knockdown of SFRP4 suppressed activation of the IL-6 amplifier in vitro and in vivo, whereas the overexpression of SFRP4 induced the activation of NF-κB-mediated transcription activity. Mechanistically, SFRP4 induced NF-κB activation by directly binding to molecules of the ubiquitination SFC complex, such as IkBα and βTrCP, followed by IkBα degradation. Furthermore, SFRP4 expression was significantly increased in fibroblasts derived from DC patients bearing the risk alleles. Consistently, fibroblasts with the risk alleles enhanced activation of the IL-6 amplifier. These findings indicate that the IL-6 amplifier is involved in the pathogenesis of DC, particularly in patients harboring the SFRP4 risk alleles. Therefore, SFRP4 is a potential therapeutic target for various inflammatory diseases and disorders, including DC. - Gateway reflexes are neural circuits that establish the gateway of immune cells to regulate tissue specific inflammation.
Keiichiroh Akabane, Kaoru Murakami, Masaaki Murakami
Expert opinion on therapeutic targets, 27, 6, 469, 477, 2023, [International Magazine]
English, Scientific journal, INTRODUCTION: Tissue-specific inflammatory diseases are regulated by several mechanisms. The gateway reflex and IL-6 amplifier are two mechanisms involved in diseases that depend on the inflammatory cytokine IL-6. The gateway reflex activates specific neural pathways that cause autoreactive CD4+ T cells to pass through gateways in blood vessels toward specific tissues in tissue-specific inflammatory diseases. These gateways are mediated by the IL-6 amplifier, which describes enhanced NF-κB activation in nonimmune cells including endothelial cells at specific sites. In total, we have reported six gateway reflexes defined by their triggering stimulus: gravity, pain, electric stimulation, stress, light, and joint inflammation. AREAS COVERED: This review summarizes the gateway reflex and IL-6 amplifier for the development of tissue-specific inflammatory diseases. EXPERT OPINION: We expect that the IL-6 amplifier and gateway reflex will lead to novel therapeutic and diagnostic methods for inflammatory diseases, particularly tissue-specific ones. - Regulation of NETosis and Inflammation by Cyclophilin D in Myeloperoxidase-Positive Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.
Takashi Kudo, Daigo Nakazawa, Kanako Watanabe-Kusunoki, Masatoshi Kanda, Satoka Shiratori-Aso, Nobuya Abe, Saori Nishio, Jun-Ichiro Koga, Sari Iwasaki, Takahiro Tsuji, Yuichiro Fukasawa, Miwako Yamasaki, Masahiko Watanabe, Sakiko Masuda, Utano Tomaru, Masaaki Murakami, Yasuaki Aratani, Akihiro Ishizu, Tatsuya Atsumi
Arthritis & rheumatology (Hoboken, N.J.), 75, 1, 71, 83, Jan. 2023, [International Magazine]
English, Scientific journal, OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is pathologically characterized by focal fibrinoid necrosis, in which ANCA-mediated neutrophil extracellular trap (NET) formation and subsequent endothelial cell necrosis occur. Cyclophilin D (CypD) plays an important role in mediation of cell necrosis and inflammation via the opening of mitochondrial permeability transition pores. This study was undertaken to examine the role of CypD in AAV pathogenesis. METHODS: We assessed the role and mechanism of CypD in ANCA-stimulated neutrophils in vitro by immunostaining and electron microscopy observation. We performed a comprehensive RNA-sequencing analysis on ANCA-treated murine neutrophils. To investigate the role of CypD in vivo, we assessed disease features in CypD-knockout mice and wild-type mice using 2 different murine AAV models: anti-myeloperoxidase IgG transfer-induced AAV and spontaneous AAV. RESULTS: In vitro experiments showed that pharmacologic and genetic inhibition of CypD suppressed ANCA-induced NET formation via the suppression of reactive oxygen species and cytochrome c release from the mitochondria. RNA-sequencing analyses in ANCA-treated murine neutrophils revealed the involvement of inflammatory responses, with CypD deficiency reducing ANCA-induced alterations in gene expression. Furthermore, analyses of upstream regulators revealed the relevance of intracellular calcium (CypD activator) and cyclosporin (CypD inhibitor) in ANCA stimulation, indicating that the CypD-dependent opening of mitochondrial permeability transition pores is associated with ANCA-induced neutrophil activation and NETosis. In both AAV mouse models, the genetic deletion of CypD ameliorated crescentic glomerulonephritis via the inhibition of CypD-dependent neutrophil and endothelial necrosis. CONCLUSION: CypD targeting is a novel and specific therapeutic strategy for AAV via the resolution of necrotizing vasculitis. - SARS-CoV-2 Omicron detection by antigen tests using saliva.
Kaoru Murakami, Sumio Iwasaki, Satoshi Oguri, Kumiko Tanaka, Rigel Suzuki, Kasumi Hayasaka, Shinichi Fujisawa, Chiaki Watanabe, Satoshi Konno, Isao Yokota, Takasuke Fukuhara, Masaaki Murakami, Takanori Teshima
Journal of clinical virology plus, 2, 4, 100109, 100109, Nov. 2022, [International Magazine]
English, Scientific journal, The Omicron emerged in November 2021 and became the predominant SARS-CoV-2 variant globally. It spreads more rapidly than ancestral lineages and its rapid detection is critical for the prevention of disease outbreaks. Antigen tests such as immunochromatographic assay (ICA) and chemiluminescent enzyme immunoassay (CLEIA) yield results more quickly than standard polymerase chain reaction (PCR). However, their utility for the detection of the Omicron variant remains unclear. We herein evaluated the performance of ICA and CLEIA in saliva from 51 patients with Omicron and 60 PCR negative individuals. The sensitivity and specificity of CLEIA were 98.0% (95%CI: 89.6-100.0%) and 100.0% (95%CI: 94.0-100.0%), respectively, with fine correlation with cycle threshold (Ct) values. The sensitivity and specificity of ICA were 58.8% (95%CI: 44.2-72.4%) and 100.0% (95%CI: 94.0-100.0%), respectively. The sensitivity of ICA was 100.0% (95%CI: 80.5-100.0%) when PCR Ct was less than 25. The Omicron can be efficiently detected in saliva by CLEIA. ICA also detects high viral load Omicron using saliva. - Interleukin-17A released from intestinal γδT cells induces cytokine storm in mice with severe dengue
Takeshi Kurosu, Daisuke Okuzaki, Yusuke Sakai, Mohamad Al Kadi, Supranee Phanthanawiboon, Yasusi Ami, Masayuki Shimojima, Tomoki Yoshikawa, Shuetsu Fukushi, Noriyo Nagata, Tadaki Suzuki, Daisuke Kamimura, Masaaki Murakami, Hideki Ebihara, Masayuki Saijo
16 Sep. 2022 - 【自己免疫疾患 層別化する新時代へ 臨床検体のマルチオミクス解析、腸内細菌によって見えてきた免疫経路の全容】(第2章)自己免疫疾患の基盤メカニズムの最新知見 ゲートウェイ反射による自己免疫疾患の制御
村上 薫, 西 李依子, 北條 慎太郎, 田中 勇希, 村上 正晃
実験医学, 40, 15, 2456, 2466, (株)羊土社, Sep. 2022
Japanese - Pathogenic neuropsychiatric effect of stress-induced microglial interleukin 12/23 axis in systemic lupus erythematosus.
Nobuya Abe, Masato Tarumi, Yuichiro Fujieda, Nobuhiko Takahashi, Kohei Karino, Mona Uchida, Michihito Kono, Yuki Tanaka, Rie Hasebe, Masaru Kato, Olga Amengual, Yoshiyuki Arinuma, Kenji Oku, Wakiro Sato, Khin Khin Tha, Miwako Yamasaki, Masahiko Watanabe, Tatsuya Atsumi, Masaaki Murakami
Annals of the rheumatic diseases, 81, 11, 1564, 1575, 11 Jul. 2022, [International Magazine]
English, Scientific journal, OBJECTIVES: The central nervous system disorder in systemic lupus erythematosus (SLE), called neuropsychiatric lupus (NPSLE), is one of the most severe phenotypes with various clinical symptoms, including mood disorder, psychosis and delirium as diffuse neuropsychological manifestations (dNPSLE). Although stress is one of the aggravating factors for neuropsychiatric symptoms, its role in the pathogenesis of dNPSLE remains to be elucidated. We aimed to investigate stress effects on the neuropsychiatric pathophysiology in SLE using lupus-prone mice and patients' data. METHODS: Sleep disturbance stress (SDS) for 2 weeks was placed on 6-8-week-old female MRL/lpr and control mice. Behavioural phenotyping, histopathological analyses and gene and protein expression analyses were performed to assess SDS-induced neuroimmunological alterations. We also evaluated cytokines of the cerebrospinal fluid and brain regional volumes in patients with dNPSLE and patients with non-dNPSLE. RESULTS: SDS-subjected MRL/lpr mice exhibited less anxiety-like behaviour, whereas stressed control mice showed increased anxiety. Furthermore, stress strongly activated the medial prefrontal cortex (mPFC) in SDS-subjected MRL/lpr. A transcriptome analysis of the PFC revealed the upregulation of microglial activation-related genes, including Il12b. We confirmed that stress-induced microglial activation and the upregulation of interleukin (IL) 12/23p40 proteins and increased dendritic spines in the mPFC of stressed MRL/lpr mice. IL-12/23p40 neutralisation and tyrosine kinase 2 inhibition mitigated the stress-induced neuropsychiatric phenotypes of MRL/lpr mice. We also found a higher level of cerebrospinal fluid IL-12/23p40 and more atrophy in the mPFC of patients with dNPSLE than those with non-dNPSLE. CONCLUSIONS: The microglial IL-12/23 axis in the mPFC might be associated with the pathogenesis and a promising therapeutic target for dNPSLE. - 【基盤病態としての慢性炎症】IL-6アンプおよびゲートウェイ反射による関節リウマチ発症メカニズム
田中 勇希, 長谷部 理絵, 村上 正晃
医学のあゆみ, 282, 1, 92, 99, 医歯薬出版(株), Jul. 2022
Japanese - ATP spreads inflammation to other limbs through crosstalk between sensory neurons and interneurons.
Rie Hasebe, Kaoru Murakami, Masaya Harada, Nada Halaka, Hiroshi Nakagawa, Fuminori Kawano, Yoshinobu Ohira, Tadafumi Kawamoto, Fiona E Yull, Timothy S Blackwell, Junko Nio-Kobayashi, Toshihiko Iwanaga, Masahiko Watanabe, Nobuhiro Watanabe, Harumi Hotta, Toshihide Yamashita, Daisuke Kamimura, Yuki Tanaka, Masaaki Murakami
The Journal of experimental medicine, 219, 6, 06 Jun. 2022, [International Magazine]
English, Scientific journal, Neural circuits between lesions are one mechanism through which local inflammation spreads to remote positions. Here, we show the inflammatory signal on one side of the joint is spread to the other side via sensory neuron-interneuron crosstalk, with ATP at the core. Surgical ablation or pharmacological inhibition of this neural pathway prevented inflammation development on the other side. Mechanistic analysis showed that ATP serves as both a neurotransmitter and an inflammation enhancer, thus acting as an intermediary between the local inflammation and neural pathway that induces inflammation on the other side. These results suggest blockade of this neural pathway, which is named the remote inflammation gateway reflex, may have therapeutic value for inflammatory diseases, particularly those, such as rheumatoid arthritis, in which inflammation spreads to remote positions. - 多発性硬化症モデル動物におけるMaresin-1の保護効果
菅原 季起, 田中 勇希, 北條 慎太郎, 村上 正晃, 南 雅文
日本薬学会年会要旨集, 142年会, 27F, pm10S, (公社)日本薬学会, Mar. 2022
Japanese - Glycogen synthase kinase 3β/CCR6-positive bone marrow cells correlate with disease activity in multicentric Castleman disease-TAFRO.
Nobuya Abe, Michihito Kono, Michihiro Kono, Naoki Ohnishi, Tomoya Sato, Masato Tarumi, Masaru Yoshimura, Taiki Sato, Kohei Karino, Yuka Shimizu, Yuichiro Fujieda, Masaru Kato, Rie Hasebe, Kenji Oku, Masaaki Murakami, Tatsuya Atsumi
British journal of haematology, 196, 5, 1194, 1204, Mar. 2022, [International Magazine]
English, Scientific journal, Multicentric Castleman disease-thrombocytopenia, anasarca, reticulin fibrosis of bone marrow, renal dysfunction and organomegaly (MCD-TAFRO)-is an emergent phenotype characterized by lymphoproliferation, fluid collection, hemocytopenia and multiple organopathy. Although studies have demonstrated an aberrant blood cytokine/chemokine profile referred to as "chemokine storm", the pathogenesis remains unclear. We aimed to identify pathogenic key molecules, potential diagnostic targets and therapeutic markers in MCD-TAFRO using serum cytokine/chemokine profiles. We performed the targeted cytokine/chemokine multiplex analysis in six cases of MCD-TAFRO with remission or non-remission status. We observed significant changes in serum concentrations of CCL2, CCL5, and Chitinase-3-like-1 in the MCD-TAFRO patients with active state compared to inactive state. Ingenuity pathway analysis revealed that glycogen synthase kinase 3 (GSK3) and CCR6, which is expressed in megakaryocytes, were detected as upstream positive regulators for activating MCD-TAFRO status. More GSK3β+ CCR6+ cells like megakaryocytes were detected in the bone marrow of patients with MCD-TAFRO than in those with systemic lupus erythematosus, MCD-not otherwise specified or autoimmune haemophagocytic lymphohistiocytosis. The cellularity of GSK3β+ CCR6+ cells was correlated with disease activity, including thrombocytopenia and anaemia. In conclusion, GSK3β and CCR6 of bone marrow cells were potentially involved in the pathogenesis of MCD-TAFRO and may act as diagnostic targets and therapeutic markers. - Cytokine and chemokine multiplex analysis-based exploration for potential treatment and prognostic prediction in large-vessel vasculitis: A preliminary observational study.
Nobuya Abe, Michihiro Kono, Michihito Kono, Takayuki Katsuyama, Kazumasa Ohmura, Taiki Sato, Kohei Karino, Yuichiro Fujieda, Masaru Kato, Rie Hasebe, Masaaki Murakami, Tatsuya Atsumi
Frontiers in immunology, 13, 1066916, 1066916, 2022, [International Magazine]
English, Scientific journal, Large-vessel vasculitis (LVV) is subclassified into two phenotypes; Takayasu arteritis and giant cell arteritis. Although the pathogenesis of LVV is not fully established, IL-6-IL-17 axis and IL-12-IFN-γ axis play critical roles in the disease development. We aimed to clarify the association between the disease state and cytokine/chemokine levels, to assess disease course as prognosis and to predict regulators in patients with LVV using the blood profiles of multiple cytokines/chemokines. This retrospective analysis comprised 35 LVV patients whose blood were collected, and multiplex cytokine/chemokine analysis with 28 analytes was performed. The differences of cytokines/chemokines corresponding disease status, upstream regulator analysis, pathway analysis and cluster analysis were conducted using the cytokines/chemokines profile. Relapse-free survival rate was calculated with Kaplan-Meier analysis in the classified clusters. In the robust analysis, IL-4, CCL2/MCP-1, TNFSF13/APRIL, TNFSF13B/BAFF, CHI3L1 and VEGF-A levels were significantly changed after treatment. Untreated LVV patients demonstrated activation of NFκB-related molecules and these patients are potentially treated with JAK/STAT inhibitors, anti-TNF-α inhibitors and IL-6 inhibitors. Cluster analysis in active LVV patients revealed two clusters including one with high blood levels of IL-1β, IL-6, IL-17, IL-23 and CCL20/MIP-3. A subgroup of the LVV patients showed activated IL-17 signature with high relapse frequency, and JAK/TyK2 inhibitors and IFN-γ inhibitors were detected as potentially upstream inhibitors. Blood cytokine/chemokine profiles would be useful for prediction of relapse and potentially contributes to establish therapeutic strategy as precision medicine in LVV patients. - Cyclophilin D regulates NETosis and inflammation in myeloperoxidase‐antineutrophil cytoplasmic antibody‐associated vasculitis
Takashi Kudo, Daigo Nakazawa, Kanako Watanabe‐Kusunoki, Masatoshi Kanda, Satoka Shiratori‐Aso, Nobuya Abe, Saori Nishio, Jun‐Ichiro Koga, Sari Iwasaki, Takahiro Tsuji, Yuichiro Fukasawa, Miwako Yamasaki, Masahiko Watanabe, Sakiko Masuda, Utano Tomaru, Masaaki Murakami, Yasuaki Aratani, Akihiro Ishizu, Tatsuya Atsumi
Arthritis & Rheumatology, in press, 1, 71, 83, Wiley, 2022, [Peer-reviewed], [International Magazine]
English, Scientific journal, OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is pathologically characterized by focal fibrinoid necrosis, in which ANCA-mediated neutrophil extracellular trap (NET) formation and subsequent endothelial cell necrosis occur. Cyclophilin D (CypD) plays an important role in mediation of cell necrosis and inflammation via the opening of mitochondrial permeability transition pores. This study was undertaken to examine the role of CypD in AAV pathogenesis. METHODS: We assessed the role and mechanism of CypD in ANCA-stimulated neutrophils in vitro by immunostaining and electron microscopy observation. We performed a comprehensive RNA-sequencing analysis on ANCA-treated murine neutrophils. To investigate the role of CypD in vivo, we assessed disease features in CypD-knockout mice and wild-type mice using 2 different murine AAV models: anti-myeloperoxidase IgG transfer-induced AAV and spontaneous AAV. RESULTS: In vitro experiments showed that pharmacologic and genetic inhibition of CypD suppressed ANCA-induced NET formation via the suppression of reactive oxygen species and cytochrome c release from the mitochondria. RNA-sequencing analyses in ANCA-treated murine neutrophils revealed the involvement of inflammatory responses, with CypD deficiency reducing ANCA-induced alterations in gene expression. Furthermore, analyses of upstream regulators revealed the relevance of intracellular calcium (CypD activator) and cyclosporin (CypD inhibitor) in ANCA stimulation, indicating that the CypD-dependent opening of mitochondrial permeability transition pores is associated with ANCA-induced neutrophil activation and NETosis. In both AAV mouse models, the genetic deletion of CypD ameliorated crescentic glomerulonephritis via the inhibition of CypD-dependent neutrophil and endothelial necrosis. CONCLUSION: CypD targeting is a novel and specific therapeutic strategy for AAV via the resolution of necrotizing vasculitis. - Depletion of Retinal Dopaminergic Activity in a Mouse Model of Rod Dysfunction Exacerbates Experimental Autoimmune Uveoretinitis: A Role for the Gateway Reflex.
Andrea Stofkova, Miloslav Zloh, Dominika Andreanska, Ivana Fiserova, Jan Kubovciak, Jan Hejda, Patrik Kutilek, Masaaki Murakami
International journal of molecular sciences, 23, 1, 31 Dec. 2021, [International Magazine]
English, Scientific journal, The gateway reflex is a mechanism by which neural inputs regulate chemokine expression at endothelial cell barriers, thereby establishing gateways for the invasion of autoreactive T cells into barrier-protected tissues. In this study, we hypothesized that rod photoreceptor dysfunction causes remodeling of retinal neural activity, which influences the blood-retinal barrier and the development of retinal inflammation. We evaluated this hypothesis using Gnat1rd17 mice, a model of night blindness with late-onset rod-cone dystrophy, and experimental autoimmune uveoretinitis (EAU). Retinal remodeling and its effect on EAU development were investigated by transcriptome profiling, target identification, and functional validation. We showed that Gnat1rd17 mice primarily underwent alterations in their retinal dopaminergic system, triggering the development of an exacerbated EAU, which was counteracted by dopamine replacement with L-DOPA administered either systemically or locally. Remarkably, dopamine acted on retinal endothelial cells to inhibit NF-κB and STAT3 activity and the expression of downstream target genes such as chemokines involved in T cell recruitment. These results suggest that rod-mediated dopamine release functions in a gateway reflex manner in the homeostatic control of immune cell entry into the retina, and the loss of retinal dopaminergic activity in conditions associated with rod dysfunction increases the susceptibility to autoimmune uveitis. - 【コロナウイルス感染の免疫学】サイトカインストームとIL-6アンプ
村上 薫, 北條 慎太郎, 田中 くみ子, 村上 正晃
炎症と免疫, 30, 1, 18, 27, (株)先端医学社, Dec. 2021
Japanese - The gateway reflex: breaking through the blood barriers.
Kaoru Murakami, Yuki Tanaka, Masaaki Murakami
International immunology, 33, 12, 743, 748, 25 Nov. 2021, [International Magazine]
English, Scientific journal, We have been studying inflammatory diseases, with a special focus on IL-6, and discovered two concepts related to inflammation development. One is the gateway reflex, which is induced by the activation of specific neural circuits followed by establishing gateways for autoreactive CD4+ T cells to pass through blood barriers toward the central nervous system (CNS) and retina during tissue-specific inflammatory diseases. We found that the formation of these gateways is dependent on the IL-6 amplifier, which is machinery for enhanced NF-κB activation in endothelial cells at specific sites. We have found five gateway reflexes in total. Here, we introduce the gateway reflex and the IL-6 amplifier. - 関節リウマチにおける軟骨細胞の新たな役割 IL-6アンプとTMEM147
太田 光俊, 田中 勇希, 岩崎 倫政, 村上 正晃
リウマチ科, 66, 4, 393, 403, (有)科学評論社, Oct. 2021
Japanese - 【脳とからだ】腸,免疫系,脳の相互作用 ゲートウェイ反射による血液脳関門への免疫細胞ゲート形成制御と病態の誘導
田中 勇希, 村上 正晃
生体の科学, 72, 5, 405, 408, (公財)金原一郎記念医学医療振興財団, Oct. 2021
Japanese - Sjögren's syndrome-associated SNPs increase GTF2I expression in salivary gland cells to enhance inflammation development.
Shuhei Shimoyama, Ikuma Nakagawa, Jing-Jing Jiang, Isao Matsumoto, John A Chiorini, Yoshinori Hasegawa, Osamu Ohara, Rie Hasebe, Mitsutoshi Ota, Mona Uchida, Daisuke Kamimura, Shintaro Hojyo, Yuki Tanaka, Tatsuya Atsumi, Masaaki Murakami
International immunology, 33, 8, 423, 434, 23 Jul. 2021, [International Magazine]
English, Scientific journal, Sjögren's syndrome (SS) is an autoimmune disease characterized by inflammation with lymphoid infiltration and destruction of the salivary glands. Although many genome-wide association studies have revealed disease-associated risk alleles, the functions of the majority of these alleles are unclear. Here, we show previously unrecognized roles of GTF2I molecules by using two SS-associated single nucleotide polymorphisms (SNPs), rs73366469 and rs117026326 (GTF2I SNPs). We found that the risk alleles of GTF2I SNPs increased GTF2I expression and enhanced nuclear factor-kappa B (NF-κB) activation in human salivary gland cells via the NF-κB p65 subunit. Indeed, the knockdown of GTF2I suppressed inflammatory responses in mouse endothelial cells and in vivo. Conversely, the over-expression of GTF2I enhanced NF-κB reporter activity depending on its p65-binding N-terminal leucine zipper domain. GTF2I is highly expressed in the human salivary gland cells of SS patients expressing the risk alleles. Consistently, the risk alleles of GTF2I SNPs were strongly associated with activation of the IL-6 amplifier, which is hyperactivation machinery of the NF-κB pathway, and lymphoid infiltration in the salivary glands of SS patients. These results demonstrated that GTF2I expression in salivary glands is increased in the presence of the risk alleles of GTF2I SNPs, resulting in activation of the NF-κB pathway in salivary gland cells. They also suggest that GTF2I could be a new therapeutic target for SS. - Gateway reflexes, neuronal circuits that regulate the gateways for autoreactive T cells in organs that have blood barriers.
Mona Uchida, Reiji Yamamoto, Shiina Matsuyama, Kaoru Murakami, Rie Hasebe, Shintaro Hojyo, Yuki Tanaka, Masaaki Murakami
International immunology, 12 May 2021, [International Magazine]
English, Scientific journal, Gateway reflexes are neural circuits that maintain homeostasis of the immune system. They form gateways for autoreactive T cells to infiltrate the central nervous system in a noradrenaline-dependent manner despite the blood-brain barrier. This mechanism is critical not only for maintaining organ homeostasis but also for inflammatory disease development. Gateway reflexes can be regulated by environmental or artificial stimuli including electrical stimulation, suggesting that the infiltration of immune cells can be controlled by bioelectronic medicine. In this review, we describe the discovery of gateway reflexes and their future directions with special focus on bioelectronic medicine. - Triazolopyrimidine derivative NK026680 and donor-specific transfusion induces CD4+CD25+Foxp3+ T cells and ameliorates allograft rejection in an antigen-specific manner.
Shin Emoto, Susumu Shibasaki, Akihisa Nagatsu, Ryoichi Goto, Hitoshi Ono, Yasutomo Fukasaku, Rumi Igarashi, Takuji Ota, Moto Fukai, Tsuyoshi Shimamura, Kan Saiga, Akinobu Taketomi, Masaaki Murakami, Satoru Todo, Kenichiro Yamashita
Transplant immunology, 65, 101338, 101338, Apr. 2021, [International Magazine]
English, Scientific journal, We have previously demonstrated the unique properties of a new triazolopyrimidine derivative, NK026680, which exerts immunosuppressive effects in rat heart transplant model and confers tolerogeneic properties on ex vivo-conditioned dendritic cells in mice. We herein demonstrate that NK026680 promotes the expansion of regulatory T cells (Tregs) with potent immunoregulatory effects when used in combination with donor-specific transfusion (DST). BALB/c (H-2d) heart graft were transplanted into C57BL/6 (H-2b) mice following intravenous injection of donor splenocytes (DST) and oral administration of NK026680. The NK026680 plus DST treatment markedly prolonged the survival time of the donor-graft, but not that of the 3rd party-graft (C3H; H-2k). Treg cells in the recipient spleen on day 0 expanded when stimulated with donor-antigens in vivo and in vitro. After heart transplantation, Treg cells accumulated into the graft and increased in the spleen. NK026680 plus DST also decreased activated CD8+ T cells in the spleen and inhibited infiltration of CD8+ T cells into the graft. Depletion of CD25+ cells inhibited the graft prolonging effect of the NK026680 plus DST treatment. NK026680 administration together with DST induces potent immunoregulatory effects in an antigen-specific manner, likely due to the in vivo generation of donor-specific Tregs. - 【免疫系の暴走 サイトカインストーム 多様な疾患で生じる全身性の炎症反応その共通機構から病態を理解する】IL-6アンプとCOVID-19におけるサイトカインストーム誘導機構
内田 萌菜, 田中 くみ子, 北條 慎太郎, 田中 勇希, 長谷部 理絵, 村上 正晃
実験医学, 39, 4, 499, 504, (株)羊土社, Mar. 2021
Japanese - COVID-19 サイトカインストームとリンパ球機能
北條 慎太郎, 内田 萌菜, 田中 くみ子, 長谷部 理絵, 村上 正晃
臨床免疫・アレルギー科, 75, 1, 94, 100, (有)科学評論社, Jan. 2021
Japanese - 新型コロナウイルス感染症(COVID-19)におけるサイトカインストーム
高橋 郁子, 木田 博朗, 田中 くみ子, 北條 慎太郎, 長谷部 理絵, 村上 正晃
老年内科, 3, 1, 74, 82, (有)科学評論社, Jan. 2021
Japanese - Rhodobacter azotoformans LPS (RAP99-LPS) Is a TLR4 Agonist That Inhibits Lung Metastasis and Enhances TLR3-Mediated Chemokine Expression.
Kaoru Murakami, Daisuke Kamimura, Rie Hasebe, Mona Uchida, Nobuya Abe, Reiji Yamamoto, Jing-Jing Jiang, Yasuhiro Hidaka, Yuko Nakanishi, Shuzo Fujita, Yuki Toda, Nobuhiro Toda, Hiroki Tanaka, Shizuo Akira, Yuki Tanaka, Masaaki Murakami
Frontiers in immunology, 12, 675909, 675909, 2021, [International Magazine]
English, Scientific journal, The lipopolysaccharides (LPSs) of Rhodobacter are reported to be TLR4 antagonists. Accordingly, the extract of Rhodobacter azotoformans (RAP99) is used as a health supplement for humans and animals in Japan to regulate immune responses in vivo. We previously analyzed the LPS structure of RAP99 (RAP99-LPS) and found it is different from that of E. coli-LPS but similar to lipid A from Rhodobacter sphaeroides (RSLA), a known antagonist of TLR4, with both having three C14 fatty acyl groups, two C10 fatty acyl groups, and two phosphates. Here we show that RAP99-LPS has an immune stimulatory activity and acts as a TLR4 agonist. Pretreatment of RAP99-LPS suppressed E. coli-LPS-mediated weight loss, suggesting it is an antagonist against E. coli-LPS like other LPS isolated from Rhodobacter. However, injections of RAP99-LPS caused splenomegaly and increased immune cell numbers in C57BL/6 mice but not in C3H/HeJ mice, suggesting that RAP99-LPS stimulates immune cells via TLR4. Consistently, RAP99-LPS suppressed the lung metastasis of B16F1 tumor cells and enhanced the expression of TLR3-mediated chemokines. These results suggest that RAP99-LPS is a TLR4 agonist that enhances the activation status of the immune system to promote anti-viral and anti-tumor activity in vivo. - 腎移植後慢性拒絶反応診断のためのLiquid Biopsy 炎症回路に関わる新規尿中バイオマーカーの研究
高田 祐輔, 上村 大輔, 樋口 はるか, 岩見 大基, 堀田 記世彦, 岩原 直也, 篠原 信雄, 村上 正晃
日本泌尿器科学会総会, 108回, 872, 872, (一社)日本泌尿器科学会総会事務局, Dec. 2020
Japanese - 【新型コロナウイルス感染症(COVID-19)-私たちが今知っておくべきこと】新型コロナウイルス感染症(COVID-19)重症化のメカニズム
長谷部 理絵, 北條 慎太郎, 田中 勇希, 内田 萌菜, 村上 正晃
カレントテラピー, 38, 12, 1145, 1150, (株)ライフメディコム, Dec. 2020
Japanese - Bidirectional communication between neural and immune systems.
Daisuke Kamimura, Yuki Tanaka, Rie Hasebe, Masaaki Murakami
International immunology, 32, 11, 693, 701, 20 Oct. 2020, [International Magazine]
English, Scientific journal, The immune and nervous systems share many features, including receptor and ligand expression, enabling efficient communication between the two. Accumulating evidence suggests that the communication is bidirectional, with the neural system regulating immune cell functions and vice versa. Steroid hormones from the hypothalamus-pituitary-adrenal gland axis are examples of systemic regulators for this communication. Neural reflexes describe regional regulation mechanisms that are a historically new concept that helps to explain how the neural and body systems including immune system communicate. Several recently identified neural reflexes, including the inflammatory reflex and gateway reflex, significantly impact the activation status of the immune system and are associated with inflammatory diseases and disorders. Either pro-inflammatory or anti-inflammatory effects can be elicited by these neural reflexes. On the other hand, the activities of immune cells during inflammation, for example the secretion of inflammatory mediators, can affect the functions of neuronal systems via neural reflexes and modulate biological outputs via specific neural pathways. In this review article, we discuss recent advances in the understanding of bidirectional neuro-immune interactions, with a particular focus on neural reflexes. - 腎移植後慢性拒絶反応のためのLiquid Biopsy 尿中エクソソームSYT17(Synaptotagmin 17)の有用性
高田 祐輔, 上村 大輔, 樋口 はるか, 岩見 大基, 堀田 記世彦, 岩原 直也, 篠原 信雄, 村上 正晃
移植, 55, 総会臨時, 339, 339, (一社)日本移植学会, Oct. 2020
Japanese - Increased urinary exosomal SYT17 levels in chronic active antibody-mediated rejection after kidney transplantation via the IL-6 amplifier.
Yusuke Takada, Daisuke Kamimura, Jing-Jing Jiang, Haruka Higuchi, Daiki Iwami, Kiyohiko Hotta, Yuki Tanaka, Mitsutoshi Ota, Madoka Higuchi, Saori Nishio, Tatsuya Atsumi, Nobuo Shinohara, Yoshihiro Matsuno, Takahiro Tsuji, Tatsu Tanabe, Hajime Sasaki, Naoya Iwahara, Masaaki Murakami
International immunology, 32, 10, 653, 662, 30 Sep. 2020, [International Magazine]
English, Scientific journal, Chronic active antibody-mediated rejection (CAAMR) is a particular problem in kidney transplantation (KTx), and ~25% of grafts are lost by CAAMR. Further, the pathogenesis remains unclear, and there is no effective cure or marker. We previously found that a hyper NFκB-activating mechanism in non-immune cells, called the IL-6 amplifier, is induced by the co-activation of NFκB and STAT3, and that this activation can develop various chronic inflammatory diseases. Here, we show that synaptotagmin-17 (SYT17) is increased in an exosomal fraction of the urine from CAAMR patients, and that this increase is associated with activation of the IL-6 amplifier. Immunohistochemistry showed that SYT17 protein expression was increased in renal tubule cells of the CAAMR group. While SYT17 protein was not detectable in whole-urine samples by western blotting, urinary exosomal SYT17 levels were significantly elevated in the CAAMR group compared to three other histology groups (normal, interstitial fibrosis and tubular atrophy, and calcineurin inhibitors toxicity) after KTx. On the other hand, current clinical laboratory data could not differentiate the CAAMR group from these groups. These data suggest that urinary exosomal SYT17 is a potential diagnostic marker for CAAMR. - ケロイド組織で炎症が遷延するメカニズム 炎症性サイトカインIL-6とCD4陽性T細胞のケロイド線維芽細胞に対する作用
村尾 尚規, 藤田 宗純, 林 利彦, 清野 研一郎, 村上 正晃, 山本 有平
瘢痕・ケロイド治療ジャーナル, 14, 4, 6, (株)全日本病院出版会, Sep. 2020
Japanese - 【線維化 慢性疾患のキープロセス 多彩な間質細胞が織りなす組織リモデリング"fibrosis"の理解】(第2章)線維化を制御する細胞間ネットワーク 炎症の誘導機構 IL-6アンプの病気への関与
北條 慎太郎, 内田 萌菜, 村上 薫, 松山 詩菜, 田中 くみ子, 村上 正晃
実験医学, 38, 12, 2032, 2039, (株)羊土社, Aug. 2020
Japanese - Corrigendum: Orosomucoid 1 is involved in the development of chronic allograft rejection after kidney transplantation.
Haruka Higuchi, Daisuke Kamimura, Jing-Jing Jiang, Toru Atsumi, Daiki Iwami, Kiyohiko Hotta, Hiroshi Harada, Yusuke Takada, Hiromi Kanno-Okada, Kanako C Hatanaka, Yuki Tanaka, Nobuo Shinohara, Masaaki Murakami
International immunology, 32, 7, 493, 493, 26 Jun. 2020, [International Magazine]
English, Scientific journal - 【あたらしい臓器連関】ゲートウェイ反射によるあたらしい臓器機能連関
田中 勇希, 田中 くみ子, 村上 正晃
細胞, 52, 7, 352, 356, (株)ニュー・サイエンス社, Jun. 2020
Japanese - Role of Chondrocytes in the Development of Rheumatoid Arthritis Via Transmembrane Protein 147-Mediated NF-κB Activation.
Mitsutoshi Ota, Yuki Tanaka, Ikuma Nakagawa, Jing-Jing Jiang, Yasunobu Arima, Daisuke Kamimura, Tomohiro Onodera, Norimasa Iwasaki, Masaaki Murakami
Arthritis & rheumatology (Hoboken, N.J.), 72, 6, 931, 942, Jun. 2020, [International Magazine]
English, Scientific journal, OBJECTIVE: We have previously reported that the coactivation of NF-κB and STAT3 in nonimmune cells, including synovial fibroblasts, enhances the expression of NF-κB target genes and plays a role in chronic inflammation and rheumatoid arthritis (RA). This study was undertaken to examine the role of NF-κB activation in chondrocytes and better understand the pathogenesis of RA. Furthermore, transmembrane protein 147 (TMEM147) was investigated as a representative NF-κB activator in chondrocytes. METHODS: Clinical samples from RA patients were analyzed by immunohistochemistry. Specimens obtained from patients with polydactyly were used as control samples. The functional contribution of chondrocytes and TMEM147 to arthritis was examined in several murine models of RA. In vitro experiments (quantitative polymerase chain reaction, RNA interference, immunoprecipitation, and confocal microscopy) were performed to investigate the mechanism of action of TMEM147 in chondrocytes. RESULTS: Samples obtained from RA patients and mouse models of RA showed coactivation of NF-κB and STAT3 in chondrocytes (P < 0.001). This coactivation induced a synergistic expression of NF-κB targets in vitro (P < 0.01). Chondrocyte-specific deletion of STAT3 significantly suppressed the development of cytokine-induced RA (P < 0.01). TMEM147 was highly expressed in chondrocytes from RA patient samples and the mouse models of RA. Gene silencing of TMEM147 or anti-TMEM147 antibody treatment inhibited the cytokine-mediated activation of NF-κB in vitro (P < 0.01) and suppressed cytokine-induced RA in vivo (P < 0.01). Mechanistically, TMEM147 molecules acted as scaffold proteins for the NF-κB complex, which included breakpoint cluster region and casein kinase 2, and enhanced NF-κB activity. CONCLUSION: These results suggest that chondrocytes play a role in the development of RA via TMEM147-mediated NF-κB activation and indicate a novel therapeutic strategy for RA. - COVID-19: A New Virus, but a Familiar Receptor and Cytokine Release Syndrome.
Toshio Hirano, Masaaki Murakami
Immunity, 52, 5, 731, 733, 19 May 2020, [International Magazine]
English, Scientific journal, Zhou et al. (Nature) and Hoffmann et al. (Cell) identify ACE2 as a SARS-CoV-2 receptor, and the latter show its entry mechanism depends on cellular serine protease TMPRSS2. These results may explain proinflammatory cytokine release via the associated angiotestin II pathway and a possible therapeutic target via the IL-6-STAT3 axis. - How COVID-19 induces cytokine storm with high mortality.
Shintaro Hojyo, Mona Uchida, Kumiko Tanaka, Rie Hasebe, Yuki Tanaka, Masaaki Murakami, Toshio Hirano
Inflammation and regeneration, 40, 37, 37, 2020, [International Magazine]
English, Scientific journal, The newly emerging coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, China, but has rapidly spread all over the world. Some COVID-19 patients encounter a severe symptom of acute respiratory distress syndrome (ARDS) with high mortality. This high severity is dependent on a cytokine storm, most likely induced by the interleukin-6 (IL-6) amplifier, which is hyper-activation machinery that regulates the nuclear factor kappa B (NF-κB) pathway and stimulated by the simultaneous activation of IL-6-signal transducer and activator of transcription 3 (STAT3) and NF-κB signaling in non-immune cells including alveolar epithelial cells and endothelial cells. We hypothesize that IL-6-STAT3 signaling is a promising therapeutic target for the cytokine storm in COVID-19, because IL-6 is a major STAT3 stimulator, particularly during inflammation. We herein review the pathogenic mechanism and potential therapeutic targets of ARDS in COVID-19 patients. - Gateway reflex: Local neuroimmune interactions that regulate blood vessels.
Daisuke Kamimura, Takuto Ohki, Yasunobu Arima, Mitsutoshi Ota, Masaaki Murakami
Neurochemistry international, 130, 104303, 104303, Nov. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, Neuroimmunology is a research field that intersects neuroscience and immunology, with the larger aim of gaining significant insights into the pathophysiology of chronic inflammatory diseases such as multiple sclerosis. Conventional studies in this field have so far mainly dealt with immune responses in the nervous system (i.e. neuroinflammation) or systemic immune regulation by the release of glucocorticoids. On the other hand, recently accumulating evidence has indicated bidirectional interactions between specific neural activations and local immune responses. Here we discuss one such local neuroimmune interaction, the gateway reflex. The gateway reflex represents a mechanism that translates specific neural stimulations into local inflammatory outcomes by changing the state of specific blood vessels to allow immune cells to extravasate, thus forming the gateway. Several types of gateway reflex have been identified, and each regulates distinct blood vessels to create gateways for immune cells that induce local inflammation. The gateway reflex represents a novel therapeutic strategy for neuroinflammation and is potentially applicable to other inflammatory diseases in peripheral organs. - 尿中エキソソーム性KIAMタンパク質は腎移植後の活性型の抗体を介した慢性拒絶反応に関する新規の非侵襲的診断バイオマーカーである(Urinary exosomal KIAM protein is a novel non-invasive diagnostic biomarker for chronic active antibody-mediated rejection after kidney transplantation)
高田 祐輔, 上村 大輔, 樋口 はるか, 岩見 大基, 堀田 記世彦, 篠原 信雄, 村上 正晃
西日本泌尿器科, 81, 増刊, 134, 134, (一社)西日本泌尿器科学会, Oct. 2019
English - 膵癌ドライバー変異はmRNA翻訳と蛋白質プレニル化を介しARF6が駆動する癌免疫回避を促進する(Pancreatic KRAS/TP53 mutations promote ARF6-based immune evasion via activating mRNA translation and protein prenylation)
橋本 あり, 橋本 茂, 古川 聖太郎, 蔦保 暁生, 小野寺 康人, 半田 悠, 及川 司, 水上 裕輔, 西川 義浩, 児玉 裕三, 村上 正晃, 平野 聡, 佐邊 壽孝
日本癌学会総会記事, 78回, P, 3033, 日本癌学会, Sep. 2019
English - ARF6 and AMAP1 are major targets of KRAS and TP53 mutations to promote invasion, PD-L1 dynamics, and immune evasion of pancreatic cancer.
Shigeru Hashimoto, Shotaro Furukawa, Ari Hashimoto, Akio Tsutaho, Akira Fukao, Yurika Sakamura, Gyanu Parajuli, Yasuhito Onodera, Yutaro Otsuka, Haruka Handa, Tsukasa Oikawa, Soichiro Hata, Yoshihiro Nishikawa, Yusuke Mizukami, Yuzo Kodama, Masaaki Murakami, Toshinobu Fujiwara, Satoshi Hirano, Hisataka Sabe
Proceedings of the National Academy of Sciences of the United States of America, 116, 35, 17450, 17459, 27 Aug. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal - Mast cells play role in wound healing through the ZnT2/GPR39/IL-6 axis.
Keigo Nishida, Aiko Hasegawa, Satoru Yamasaki, Ryota Uchida, Wakana Ohashi, Yosuke Kurashima, Jun Kunisawa, Shunsuke Kimura, Toshihiko Iwanaga, Hiroshi Watarai, Koji Hase, Hideki Ogura, Manabu Nakayama, Jun-Ichi Kashiwakura, Yoshimichi Okayama, Masato Kubo, Osamu Ohara, Hiroshi Kiyono, Haruhiko Koseki, Masaaki Murakami, Toshio Hirano
Scientific reports, 9, 1, 10842, 10842, 25 Jul. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, Zinc (Zn) is an essential nutrient and its deficiency causes immunodeficiency and skin disorders. Various cells including mast cells release Zn-containing granules when activated; however, the biological role of the released Zn is currently unclear. Here we report our findings that Zn transporter ZnT2 is required for the release of Zn from mast cells. In addition, we found that Zn and mast cells induce IL-6 production from inflammatory cells such as skin fibroblasts and promote wound healing, a process that involves inflammation. Zn induces the production of a variety of pro-inflammatory cytokines including IL-6 through signaling pathways mediated by the Zn receptor GPR39. Consistent with these findings, wound healing was impaired in mice lacking IL-6 or GPR39. Thus, our results show that Zn and mast cells play a critical role in wound healing through activation of the GPR39/IL-6 signaling axis. - 【"適応&修復"のサイエンスと臨床応用の最前線】ゲートウェイ反射による血管・臓器調節機構
田中 勇希, 村上 正晃
別冊Bio Clinica: 慢性炎症と疾患, 8, 1, 33, 37, (株)北隆館, Jul. 2019
Japanese - Phosphorylation-dependent Regnase-1 release from endoplasmic reticulum is critical in IL-17 response.
Hiroki Tanaka, Yasunobu Arima, Daisuke Kamimura, Yuki Tanaka, Noriyuki Takahashi, Takuya Uehata, Kazuhiko Maeda, Takashi Satoh, Masaaki Murakami, Shizuo Akira
The Journal of experimental medicine, 216, 6, 1431, 1449, 03 Jun. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, Regnase-1 (also known as Zc3h12a or MCPIP-1) is an endoribonuclease involved in mRNA degradation of inflammation-associated genes. Regnase-1 is inactivated in response to external stimuli through post-translational modifications including phosphorylation, yet the precise role of phosphorylation remains unknown. Here, we demonstrate that interleukin (IL)-17 induces phosphorylation of Regnase-1 in an Act1-TBK1/IKKi-dependent manner, especially in nonhematopoietic cells. Phosphorylated Regnase-1 is released from the endoplasmic reticulum (ER) into the cytosol, thereby losing its mRNA degradation function, which leads to expression of IL-17 target genes. By using CRISPR/Cas-9 technology, we generated Regnase-1 mutant mice, in which IL-17-induced Regnase-1 phosphorylation is completely blocked. Mutant mice (Regnase-1AA/AA and Regnase-1ΔCTD/ΔCTD ) were resistant to the IL-17-mediated inflammation caused by T helper 17 (Th17) cells in vivo. Thus, Regnase-1 plays a critical role in the development of IL-17-mediated inflammatory diseases via the Act1-TBK1-IKKi axis, and blockade of Regnase-1 phosphorylation sites may be promising for treatment of Th17-associated diseases. - Pleiotropy and Specificity: Insights from the Interleukin 6 Family of Cytokines.
Masaaki Murakami, Daisuke Kamimura, Toshio Hirano
Immunity, 50, 4, 812, 831, 16 Apr. 2019, [International Magazine]
English, Scientific journal, Since the molecular cloning of interleukin-6 (IL-6) in 1986, many other cytokines have been found to share the same signal transducer, gp130, in their receptor complexes. Thus, the IL-6 family of cytokines now consists of ten members. Although some of the family members' functions are redundant as a result of the expression of gp130, there are also functional distinctions between members. The mechanisms that determine functional redundancies and distinctions are not completely understood. Yet, research has clarified the role of IL-6 family cytokines in autoimmune diseases and has led to effective therapies that target them. Here, we review the IL-6 family of cytokines in autoimmune diseases, with a particular focus on the prototypical member IL-6, from the viewpoints of their structure, signaling, and biological features and discuss possible mechanisms of their functional pleiotropy. - Photopic light-mediated down-regulation of local α1A-adrenergic signaling protects blood-retina barrier in experimental autoimmune uveoretinitis.
Andrea Stofkova, Daisuke Kamimura, Takuto Ohki, Mitsutoshi Ota, Yasunobu Arima, Masaaki Murakami
Scientific reports, 9, 1, 2353, 2353, 20 Feb. 2019, [International Magazine]
English, Scientific journal, We have reported the gateway reflex, which describes specific neural activations that regulate immune cell gateways at specific blood vessels in the central nervous system (CNS). Four types of gateway reflexes exist, all of which induce alterations in endothelial cells at specific vessels of the blood-brain barrier followed by inflammation in the CNS in the presence of CNS-autoreactive T cells. Here we report a new gateway reflex that suppresses the development of retinal inflammation by using an autoreactive T cell-mediated ocular inflammation model. Exposure to photopic light down-regulated the adrenoceptor pathway to attenuate ocular inflammation by suppressing breaching of the blood-retina barrier. Mechanistic analysis showed that exposure to photopic light down-regulates the expression of α1A-adrenoceptor (α1AAR) due to high levels of norepinephrine and epinephrine, subsequently suppressing inflammation. Surgical ablation of the superior cervical ganglion (SCG) did not negate the protective effect of photopic light, suggesting the involvement of retinal noradrenergic neurons rather than sympathetic neurons from the SCG. Blockade of α1AAR signaling under mesopic light recapitulated the protective effect of photopic light. Thus, targeting regional adrenoceptor signaling might represent a novel therapeutic strategy for autoimmune diseases including those that affect organs separated by barriers such as the CNS and eyes. - NEDD4 Is Involved in Inflammation Development during Keloid Formation.
Munezumi Fujita, Yuhei Yamamoto, Jing-Jing Jiang, Toru Atsumi, Yuki Tanaka, Takuto Ohki, Naoki Murao, Emi Funayama, Toshihiko Hayashi, Masayuki Osawa, Taku Maeda, Daisuke Kamimura, Masaaki Murakami
The Journal of investigative dermatology, 139, 2, 333, 341, Feb. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, Keloids mark a chronic inflammatory disease characterized by a fibroproliferative disorder of the skin. A genome-wide association study showed that single-nucleotide polymorphism rs8032158 in the neural precursor cell-expressed NEDD4 gene, which has six protein-coding transcript variants (TVs), is genetically linked to keloids. Here, we show that the high frequency of risk allele C in rs8032158 in keloid patients is associated with a selectively higher expression of TV3 of NEDD4 to activate the NF-κB pathway. Comparisons of keloid scars with normal skin samples that do not have the single-nucleotide polymorphism allele and were derived from different anatomical sites showed stronger expressions of NEDD4 TV3 and activated forms of NF-κB and STAT3 in keloid scars. Forced expression or selective knockdown of NEDD4 TV3 increased or decreased NF-κB activation in vitro. Furthermore, NEDD4 knockdown suppressed NF-κB-dependent inflammation development in vivo. Mechanistic analysis showed that NEDD4 TV3 is involved in NF-κB activation through its association with the adaptor protein RIP. These results suggest that NEDD4 TV3 is a potential diagnostic marker and therapeutic target for chronic skin diseases, including keloid. - Neural stimulations regulate the infiltration of immune cells into the CNS
D. Kamimura, M. Murakami
Journal of Internal Medicine, 286, 3, 259, 267, Blackwell Publishing Ltd, 2019
English, Scientific journal - Neural activity regulates autoimmune diseases through the gateway reflex.
Andrea Stofkova, Masaaki Murakami
Bioelectronic medicine, 5, 14, 14, 2019, [International Magazine]
English, Scientific journal, The brain, spinal cord and retina are protected from blood-borne compounds by the blood-brain barrier (BBB), blood-spinal cord barrier (BSCB) and blood-retina barrier (BRB) respectively, which create a physical interface that tightly controls molecular and cellular transport. The mechanical and functional integrity of these unique structures between blood vessels and nervous tissues is critical for maintaining organ homeostasis. To preserve the stability of these barriers, interplay between constituent barrier cells, such as vascular endothelial cells, pericytes, glial cells and neurons, is required. When any of these cells are defective, the barrier can fail, allowing blood-borne compounds to encroach neural tissues and cause neuropathologies. Autoimmune diseases of the central nervous system (CNS) and retina are characterized by barrier disruption and the infiltration of activated immune cells. Here we review our recent findings on the role of neural activity in the regulation of these barriers at the vascular endothelial cell level in the promotion of or protection against the development of autoimmune diseases. We suggest nervous system reflexes, which we named gateway reflexes, are fundamentally involved in these diseases. Although their reflex arcs are not completely understood, we identified the activation of specific sensory neurons or receptor cells to which barrier endothelial cells respond as effectors that regulate gateways for immune cells to enter the nervous tissue. We explain this novel mechanism and describe its role in neuroinflammatory conditions, including models of multiple sclerosis and posterior autoimmune uveitis. - Short-Term Administration of Single-Agent Toceranib in Six Cases of Inoperable Massive Canine Hepatocellular Carcinoma.
Heishima K, Iwasaki R, Kawabe M, Murakami M, Sakai H, Maruo K, Mori T
Journal of the American Animal Hospital Association, Nov. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, Six dogs with massive hepatocellular carcinoma that was not amenable to surgery were treated by oral administration of single-agent toceranib at a dose of 2.0-3.0 mg/kg every other day for a minimum of 60 days. Partial response was achieved in three dogs, stable disease was achieved in one dog, and progressive disease occurred in two dogs, according to the canine Response Evaluation Criteria in Solid Tumors v1.0. Observed adverse events were mild to moderate in severity and reported in accordance with the Veterinary Cooperative Oncology Group's common terminology criteria for adverse events v1.1. Activities of alanine aminotransferase and alkaline phosphatase decreased in the cases that were sensitive to treatment with toceranib, whereas the activities remained high in resistant cases. Additionally, the level of phospho-vascular endothelial growth factor receptor 2 was found to be increased in a resistant case. Single-agent toceranib might prove to be an effective treatment for canine hepatocellular carcinoma pending further validation. - Presenilin 1 Regulates NF-κB Activation via Association with Breakpoint Cluster Region and Casein Kinase II.
Tanaka Y, Sabharwal L, Ota M, Nakagawa I, Jiang JJ, Arima Y, Ogura H, Okochi M, Ishii M, Kamimura D, Murakami M
Journal of immunology (Baltimore, Md. : 1950), 201, 8, 2256, 2263, Oct. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, We recently reported that NF-κB-mediated inflammation caused by breakpoint cluster region (BCR) is dependent on the α subunit of casein kinase II (CK2α) complex. In the current study, we demonstrate that presenilin 1 (Psen1), which is a catalytic component of the γ-secretase complex and the mutations of which are known to cause familial Alzheimer disease, acts as a scaffold of the BCR-CK2α-p65 complex to induce NF-κB activation. Indeed, Psen1 deficiency in mouse endothelial cells showed a significant reduction of NF-κB p65 recruitment to target gene promoters. Conversely, Psen1 overexpression enhanced reporter activation under NF-κB responsive elements and IL-6 promoter. Furthermore, the transcription of NF-κB target genes was not inhibited by a γ-secretase inhibitor, suggesting that Psen1 regulates NF-κB activation in a manner independent of γ-secretase activity. Mechanistically, Psen1 associated with the BCR-CK2α complex, which is required for phosphorylation of p65 at serine 529. Consistently, TNF-α-induced phosphorylation of p65 at serine 529 was significantly decreased in Psen1-deficient cells. The association of the BCR-CK2α-p65 complex was perturbed in the absence of Psen1. These results suggest that Psen1 functions as a scaffold of the BCR-CK2α-p65 complex and that this signaling cascade could be a novel therapeutic target for various chronic inflammation conditions, including those in Alzheimer disease. - Bmi1 Regulates IκBα Degradation via Association with the SCF Complex.
Okuyama Y, Tanaka Y, Jiang JJ, Kamimura D, Nakamura A, Ota M, Ohki T, Higo D, Ogura H, Ishii N, Atsumi T, Murakami M
Journal of immunology (Baltimore, Md. : 1950), 201, 8, 2264, 2272, Oct. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, Bmi1 is a polycomb group protein and regulator that stabilizes the ubiquitination complex PRC1 in the nucleus with no evidently direct link to the NF-κB pathway. In this study, we report a novel function of Bmi1: its regulation of IκBα ubiquitination in the cytoplasm. A deficiency of Bmi1 inhibited NF-κB-mediated gene expression in vitro and a NF-κB-mediated mouse model of arthritis in vivo. Mechanistic analysis showed that Bmi1 associated with the SCF ubiquitination complex via its N terminus and with phosphorylation by an IKKα/β-dependent pathway, leading to the ubiquitination of IκBα. These effects on NF-κB-related inflammation suggest Bmi1 in the SCF complex is a potential therapeutic target for various diseases and disorders, including autoimmune diseases. - 神経系のバリアー機能と病態 ゲートウェイ反射を起点とした神経-免疫のクロストーク
田中 勇希, 村上 正晃
神経免疫学, 23, 1, 50, 50, (一社)日本神経免疫学会, Sep. 2018
Japanese - 腎移植の慢性抗体関連型拒絶反応における早期診断バイオマーカー、治療ターゲットOrosomucoid1(ORM1)の可能性
樋口 はるか, 堀田 記世彦, 岩見 大基, 村上 正晃, 篠原 信雄
移植, 53, 総会臨時, 483, 483, (一社)日本移植学会, Sep. 2018
Japanese - Anti-tumour effect of lapatinib in canine transitional cell carcinoma cell lines
Sakai K, Maeda S, Saeki K, Nakagawa T, Murakami M, Endo Y, Yonezawa T, Kadosawa T, Mori T, Nishimura R, Matsuki N
Vet Comp Oncol., 16, 4, 642, 649, Sep. 2018, [Peer-reviewed]
English, Scientific journal - Cell- and stage-specific localization of galectin-3, a β-galactoside-binding lectin, in a mouse model of experimental autoimmune encephalomyelitis
Tetsuya Itabashi, Yasunobu Arima, Daisuke Kamimura, Kotaro Higuchi, Yoshio Bando, Hiromi Takahashi-Iwanaga, Masaaki Murakami, Masahiko Watanabe, Toshihiko Iwanaga, Junko Nio-Kobayashi
Neurochemistry International, 118, 176, 184, Elsevier Ltd, 01 Sep. 2018, [Peer-reviewed]
English, Scientific journal - Chemical Landscape for Tissue Clearing based on Hydrophilic Reagents
Kazuki Tainaka, Tatsuya C. Murakam, Etsuo A. Susaki, Chika Shimizu, Rie Saito, Kei Takahashi, Akiko Hayashi-Takagi, Hiroshi Sekiya, Yasunobu Arima, Satoshi Nojima, Masako Ikemura, Tetsuo Ushiku, Yoshihiro Shimizu, Masaaki Murakami, Kenji F. Tanaka, Masamitsu Iino, Haruo Kasai, Toshikuni Sasaoka, Kazuto Kobayashi, Kohei Miyazono, Eiichi Morii, Tadashi Isa, Masashi Fukayama, Akiyoshi Kakita, Hiroki R. Ueda
Cell Reports, 24, 8, 2196, 2210, Cell Press, 24 Aug. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, We describe a strategy for developing hydrophilic chemical cocktails for tissue delipidation, decoloring, refractive index (RI) matching, and decalcification, based on comprehensive chemical profiling. More than 1,600 chemicals were screened by a high-throughput evaluation system for each chemical process. The chemical profiling revealed important chemical factors: salt-free amine with high octanol/water partition-coefficient (logP) for delipidation, N-alkylimidazole for decoloring, aromatic amide for RI matching, and protonation of phosphate ion for decalcification. The strategic integration of optimal chemical cocktails provided a series of CUBIC (clear, unobstructed brain/body imaging cocktails and computational analysis) protocols, which efficiently clear mouse organs, mouse body including bone, and even large primate and human tissues. The updated CUBIC protocols are scalable and reproducible, and they enable three-dimensional imaging of the mammalian body and large primate and human tissues. This strategy represents a future paradigm for the rational design of hydrophilic clearing cocktails that can be used for large tissues. - Differences in activated clotting time and initial heparin dosage during atrial fibrillation ablation for patients with edoxaban compared with warfarin
Hirosuke Yamaji, Takashi Murakami, Kazuyoshi Hina, Shunichi Higashiya, Hiroshi Kawamura, Masaaki Murakami, Shigeshi Kamikawa, Satoshi Hirohata, Shozo Kusachi
Journal of Cardiovascular Electrophysiology, 29, 6, 835, 843, Blackwell Publishing Inc., 01 Jun. 2018, [Peer-reviewed]
English, Scientific journal - Gateway reflex: neural activation-mediated immune cell gateways in the central nervous system.
Kamimura D, Ohki T, Arima Y, Murakami M
International immunology, 30, 7, 281, 289, Jun. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, The neural regulation of organs can be categorized as systemic or local. Whereas systemic regulation by the hypothalamus-pituitary-adrenal gland-mediated release of steroid hormones has been well studied, the mechanisms for local regulation have only recently emerged. Two types of local neural regulation are known, the gateway reflex and the inflammatory reflex. The gateway reflex describes a mechanism that converts regional neural stimulations into inflammatory outputs by changing the state of specific blood vessels. Molecularly, the enhancement of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity in endothelial cells by neurotransmitters, such as noradrenaline and ATP, induces an enhanced production of pro-inflammatory mediators, including chemokines, which form immune cell gateways at specific vessels. Several types of gateway reflex have been identified, and each regulates distinct organs by creating gateways for autoreactive T cells that induce local inflammation. On the other hand, the inflammatory reflex elicits an anti-inflammatory response through vagal nerves. Here, we summarize recent works on these two local neuro-immune interactions, giving special focus to the gateway reflex. - Existence of NEU1 sialidase on mouse thymocytes whose natural substrate is CD5
Shigeko Kijimoto-Ochiai, Tokuko Matsumoto-Mizuno, Daisuke Kamimura, Masaaki Murakami, Miwako Kobayashi, Ichiro Matsuoka, Hiroshi Ochiai, Hideharu Ishida, Makoto Kiso, Keiko Kamimura, Toshiaki Koda
Glycobiology, 28, 5, 306, 317, Oxford University Press, 01 May 2018, [Peer-reviewed]
English, Scientific journal - Verification of radiodynamic therapy by medical linear accelerator using a mouse melanoma tumor model.
Junko Takahashi, Mami Murakami, Takashi Mori, Hitoshi Iwahashi
Scientific reports, 8, 1, 2728, 2728, 09 Feb. 2018, [Peer-reviewed], [International Magazine]
English, Scientific journal, Combined treatment with 5-aminolevulinic acid (5-ALA) and X-rays improves tumor suppression in vivo. This is because the accumulated protoporphyrin IX from 5-ALA enhances the generation of ROS by the X-ray irradiation. In the present study, a high-energy medical linear accelerator was used instead of a non-medical low energy X-ray irradiator, which had been previously used. Tumor-bearing mice implanted with B16-BL6 melanoma cells were treated with fractionated doses of irradiation (in total, 20 or 30 Gy), using two types of X-ray irradiator after 5-ALA administration. Suppression of tumor growth was enhanced with X-ray irradiation in combination with 5-ALA treatment compared with X-ray treatment alone, using both medical and non-medical X-ray irradiators. 5-ALA has been used clinically for photodynamic therapy. Thus, "radiodynamic therapy", using radiation from medical linacs as a physical driving force, rather than the light used in photodynamic therapy, may have potential clinical applications. - Rbm10 regulates inflammation development via alternative splicing of Dnmt3b
Toru Atsumi, Hironao Suzuki, Jing-Jing Jiang, Yuko Okuyama, Ikuma Nakagawa, Mitsutoshi Ota, Yuki Tanaka, Takuto Ohki, Kokichi Katsunuma, Koichi Nakajima, Yoshinori Hasegawa, Osamu Ohara, Hideki Ogura, Yasunobu Arima, Daisuke Kamimura, Masaaki Murakami
International Immunology, 29, 12, 581, 591, Oxford University Press, 01 Dec. 2017, [Peer-reviewed]
English, Scientific journal - Slc3a2 Mediates Branched-Chain Amino-Acid-Dependent Maintenance of Regulatory T Cells
Kayo Ikeda, Makoto Kinoshita, Hisako Kayama, Shushi Nagamori, Pornparn Kongpracha, Eiji Umemoto, Ryu Okumura, Takashi Kurakawa, Mari Murakami, Norihisa Mikami, Yasunori Shintani, Satoko Ueno, Ayatoshi Andou, Morihiro Ito, Hideki Tsumura, Koji Yasutomo, Keiichi Ozono, Seiji Takashima, Shimon Sakaguchi, Yoshikatsu Kanai, Kiyoshi Takeda
CELL REPORTS, 21, 7, 1824, 1838, Nov. 2017, [Peer-reviewed]
English, Scientific journal - The Gateway Reflex, a Novel Neuro-immune interaction for the Regulation of Regional vessels
Yuki Tanaka, Yasunobu Arima, Daisuke Kamimura, Masaaki Murakami
FRONTIERS IN IMMUNOLOGY, 8, 1321, Oct. 2017, [Peer-reviewed]
English - Brain micro-inflammation at specific vessels dysregulates organ-homeostasis via the activation of a new neural circuit
Yasunobu Arima, Takuto Ohki, Naoki Nishikawa, Kotaro Higuchi, Mitsutoshi Ota, Yuki Tanaka, Junko Nio-Kobayashi, Mohamed Elfeky, Ryota Sakai, Yuki Mori, Tadafumi Kawamoto, Andrea Stofkova, Yukihiro Sakashita, Yuji Morimoto, Masaki Kuwatani, Toshihihiko Iwanaga, Yoshichika Yoshioka, Naoya Sakamoto, Akihiko Yoshimura, Mitsuyoshi Takiguchi, Saburo Sakoda, Marco Prinz, Daisuke Kamimura, Masaaki Murakami
ELIFE, 6, Aug. 2017, [Peer-reviewed]
English, Scientific journal - BATF2 inhibits immunopathological Th17 responses by suppressing Il23a expression during Trypanosoma cruzi infection
Shoko Kitada, Hisako Kayama, Daisuke Okuzaki, Ritsuko Koga, Masao Kobayashi, Yasunobu Arima, Atsushi Kumanogoh, Masaaki Murakami, Masahito Ikawa, Kiyoshi Takeda
JOURNAL OF EXPERIMENTAL MEDICINE, 214, 5, 1313, 1331, May 2017, [Peer-reviewed]
English, Scientific journal - Recent advances in neuroimmune interactions
Masaaki Murakami
Clinical and Experimental Neuroimmunology, 8, 1, 3, 4, Wiley-Blackwell, 01 Feb. 2017, [Peer-reviewed]
English, Scientific journal - Gateway Reflexes are Stimulated by Neural Activations and Promote the Pathogenesis of Multiple Sclerosis Models
K. Higuchi, D. Kamimura, A. Stofkova, N. Nishikawa, T. Ohki, Y. Arima, M. Murakami
Nutrition and Lifestyle in Neurological Autoimmune Diseases: Multiple Sclerosis, 39, 45, Elsevier Inc., 18 Jan. 2017, [Peer-reviewed]
English, In book - Breakpoint cluster region-mediated inflammation is dependent on casein kinase II (vol 197, pg 3111, 2016)
J. Meng, J. -J. Jiang, T. Atsumi, H. Bando, Y. Okuyama, L. Sabharwal, I. Nakagawa, H. Higuchi, M. Ota, M. Okawara, R. Ishitani, O. Nureki, D. Higo, Y. Arima, H. Ogura, D. Kamimura, M. Murakami
JOURNAL OF IMMUNOLOGY, 198, 2, 971, 971, Jan. 2017, [Peer-reviewed]
English - Inflammation amplifier and gateway reflex: The regulation of inflammation by neuroimmune interaction
Ikuma Nakagawa, Masaaki Murakami
Japanese Journal of Clinical Immunology, 40, 3, 160, 168, Japan Society for Clinical Immunology, 2017, [Peer-reviewed]
Japanese, Scientific journal - Lactobacillus helveticus SBT2171 Attenuates Experimental Autoimmune Encephalomyelitis in Mice.
Maya Yamashita, Ken Ukibe, Yumi Matsubara, Tomohiro Hosoya, Fumihiko Sakai, Shigeyuki Kon, Yasunobu Arima, Masaaki Murakami, Hisako Nakagawa, Tadaaki Miyazaki
Frontiers in microbiology, 8, 2596, 2596, 2017, [Peer-reviewed], [International Magazine]
English, Scientific journal, We recently reported that Lactobacillus helveticus SBT2171 (LH2171) inhibited the proliferation and inflammatory cytokine production of primary immune cells in vitro, and alleviated collagen-induced arthritis (CIA) in mice, a model of human rheumatoid arthritis (RA). In this study, we newly investigated whether LH2171 could relieve the severity of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), which is an autoimmune disease, but develop the symptoms by different mechanisms from RA. In MS and EAE, main cause of the disease is the abnormality in CD4+ T cell immunity, whereas in RA and CIA, is that in antibody-mediated immunity. The intraperitoneal administration of LH2171 significantly decreased the incidence and clinical score of EAE in mice. LH2171 also reduced the numbers of pathogenic immune cells, especially Th17 cells, in the spinal cord at the peak stage of disease severity. Interestingly, before the onset of EAE, LH2171 administration remarkably decreased the ratio of Th17 cells to CD4+ T cells in the inguinal lymph nodes (LNs), where pathogenic immune cells are activated to infiltrate the central nervous system, including the spinal cord. Furthermore, the expression of interleukin (IL)-6, an inflammatory cytokine essential for Th17 differentiation, decreased in the LNs of LH2171-administered mice. Moreover, LH2171 significantly inhibited IL-6 production in vitro from both DC2.4 and RAW264.7 cells, model cell lines of antigen-presenting cells. These findings suggest that LH2171 might down-regulate IL-6 production and the subsequent Th17 differentiation and spinal cord infiltration, consequently alleviating EAE symptoms. - Bacteremic kidney cyst infection caused by Helicobacter cinaedi.
Ito K, Yamamoto T, Nishio H, Sawaya A, Murakami M, Kitagawa A, Matsuo Y, Matsuo K, Tanaka S, Mori N
CEN case reports, 5, 2, 121, 124, Nov. 2016, [Peer-reviewed] - Breakpoint Cluster Region-Mediated Inflammation Is Dependent on Casein Kinase II
Jie Meng, Jing-Jing Jiang, Toru Atsumi, Hidenori Bando, Yuko Okuyama, Lavannya Sabharwal, Ikuma Nakagawa, Haruka Higuchi, Mitsutoshi Ota, Momoko Okawara, Ryuichiro Ishitani, Osamu Nureki, Daisuke Higo, Yasunobu Arima, Hideki Ogura, Daisuke Kamimura, Masaaki Murakami
JOURNAL OF IMMUNOLOGY, 197, 8, 3111, 3119, Oct. 2016, [Peer-reviewed]
English, Scientific journal - 移植腎における炎症アンプの活性化
樋口 はるか, 岩見 大基, 堀田 記世彦, 佐々木 元, 広瀬 貴行, 篠原 信雄, 村上 正晃
移植, 51, 総会臨時, 381, 381, (一社)日本移植学会, Sep. 2016
Japanese - Strong TCR-mediated signals suppress integrated stress responses induced by KDELR1 deficiency in naive T cells
Daisuke Kamimura, Yasunobu Arima, Mineko Tsuruoka, Jing-jing Jiang, Hidenori Bando, Jie Meng, Lavannya Sabharwal, Andrea Stofkova, Naoki Nishikawa, Kotaro Higuchi, Hideki Ogura, Toru Atsumi, Masaaki Murakami
INTERNATIONAL IMMUNOLOGY, 28, 3, 117, 126, Mar. 2016, [Peer-reviewed]
English, Scientific journal - Interleukin-6
D. Kamimura, T. Hirano, M. Murakami
The Curated Reference Collection in Neuroscience and Biobehavioral Psychology, 430, 439, Elsevier Science Ltd., 01 Jan. 2016
English, In book - Adenovirus-mediated ICOSIg gene therapy in a presensitized murine model of allergic rhinitis
Jun Sato, Nobuhiro Konno, Masaaki Murakami, Toshimitsu Uede, Tetsuo Himi
Advances in Oto-Rhino-Laryngology, 77, 59, 66, S. Karger AG, 2016, [Peer-reviewed]
English, Scientific journal - Epidemiological study of canine neoplasia based on tumor registration data of domestic dogs in Gifu prefecture between April 2013 and March 2014.
Komazawa S, Shibata S, Sakai S, Ito Y, Kawabe M, Murakami M, Mori M, Maruo K
J Jpn Vet Med Assoc, 69, 7, 395, 400, 日本獣医師会, 2016, [Peer-reviewed]
Japanese - KDELR1はナイーブT細胞において統合ストレス応答を調節する
上村 大輔, 勝沼 功吉, 有馬 康伸, 熱海 徹, Jiang Jing-Jing, 板東 秀典, Meng Jie, Sabharwal Lavannya, Stofkova Andrea, 西川 直樹, 鈴木 宏尚, 小椋 英樹, 植田 尚子, 鶴岡 峰子, 原田 誠也, 小林 純也, 長谷川 孝徳, 吉田 尚弘, 古関 明彦, 三浦 郁生, 若菜 茂晴, 西田 圭吾, 北村 秀光, 深田 俊幸, 平野 俊夫, 村上 正晃
日本生化学会大会・日本分子生物学会年会合同大会講演要旨集, 88回・38回, [1LBA045], [1LBA045], (公社)日本生化学会, Dec. 2015
English - Naive T Cell Homeostasis Regulated by Stress Responses and TCR Signaling
Daisuke Kamimura, Toru Atsumi, Andrea Stofkova, Naoki Nishikawa, Takuto Ohki, Hironao Suzuki, Kokichi Katsunuma, Jing-jing Jiang, Hidenori Bando, Jie Meng, Lavannya Sabharwal, Hideki Ogura, Toshio Hirano, Yasunobu Arima, Masaaki Murakami
FRONTIERS IN IMMUNOLOGY, 6, 638, Dec. 2015, [Peer-reviewed]
English - Klotho-related Molecules Upregulated by Smoking Habit in Apparently Healthy Men: A Cross-sectional Study
Kaori Nakanishi, Makoto Nishida, Masaya Harada, Tohru Ohama, Noritaka Kawada, Masaaki Murakami, Toshiki Moriyama, Keiko Yamauchi-Takihara
SCIENTIFIC REPORTS, 5, 14230, Sep. 2015, [Peer-reviewed]
English, Scientific journal - Role of T cell—glial cell interactions in creating and amplifying central nervous system inflammation and multiple sclerosis disease symptoms
Eric S. Huseby, Daisuke Kamimura, Yasunobu Arima, Caitlin S. Parello, Katsuhiro Sasaki, Masaaki Murakami
Frontiers in Cellular Neuroscience, 9, AUGUST, 295, Frontiers Media S.A., 05 Aug. 2015, [Peer-reviewed]
English - CD147/Basigin Limits Lupus Nephritis and Th17 Cell Differentiation in Mice by Inhibiting the Interleukin-6/STAT-3 Pathway
Kayaho Maeda, Tomoki Kosugi, Waichi Sato, Hiroshi Kojima, Yuka Sato, Daisuke Kamimura, Noritoshi Kato, Naotake Tsuboi, Yukio Yuzawa, Seiichi Matsuo, Masaaki Murakami, Shoichi Maruyama, Kenji Kadomatsu
ARTHRITIS & RHEUMATOLOGY, 67, 8, 2185, 2195, Aug. 2015, [Peer-reviewed]
English, Scientific journal - mTOR Complex Signaling through the SEMA4A-Plexin B2 Axis Is Required for Optimal Activation and Differentiation of CD8+ T Cells.
Daisuke Ito, Satoshi Nojima, Masayuki Nishide, Tatsusada Okuno, Hyota Takamatsu, Sujin Kang, Tetsuya Kimura, Yuji Yoshida, Keiko Morimoto, Yohei Maeda, Takashi Hosokawa, Toshihiko Toyofuku, Jun Ohshima, Daisuke Kamimura, Masahiro Yamamoto, Masaaki Murakami, Eiichi Morii, Hiromi Rakugi, Yoshitaka Isaka, Atsushi Kumanogoh
Journal of immunology (Baltimore, Md. : 1950), 195, 3, 934, 43, 01 Aug. 2015, [Peer-reviewed], [International Magazine]
English, Scientific journal, Mammalian target of rapamycin (mTOR) plays crucial roles in activation and differentiation of diverse types of immune cells. Although several lines of evidence have demonstrated the importance of mTOR-mediated signals in CD4(+) T cell responses, the involvement of mTOR in CD8(+) T cell responses is not fully understood. In this study, we show that a class IV semaphorin, SEMA4A, regulates CD8(+) T cell activation and differentiation through activation of mTOR complex (mTORC) 1. SEMA4A(-/-) CD8(+) T cells exhibited impairments in production of IFN-γ and TNF-α and induction of the effector molecules granzyme B, perforin, and FAS-L. Upon infection with OVA-expressing Listeria monocytogenes, pathogen-specific effector CD8(+) T cell responses were significantly impaired in SEMA4A(-/-) mice. Furthermore, SEMA4A(-/-) CD8(+) T cells exhibited reduced mTORC1 activity and elevated mTORC2 activity, suggesting that SEMA4A is required for optimal activation of mTORC1 in CD8(+) T cells. IFN-γ production and mTORC1 activity in SEMA4A(-/-) CD8(+) T cells were restored by administration of recombinant Sema4A protein. In addition, we show that plexin B2 is a functional receptor of SEMA4A in CD8(+) T cells. Collectively, these results not only demonstrate the role of SEMA4A in CD8(+) T cells, but also reveal a novel link between a semaphorin and mTOR signaling. - A pain-mediated neural signal induces relapse in murine autoimmune encephalomyelitis, a multiple sclerosis model
Yasunobu Arima, Daisuke Kamimura, Toru Atsumi, Masaya Harada, Tadafumi Kawamoto, Naoki Nishikawa, Andrea Stofkova, Takuto Ohki, Kotaro Higuchi, Yuji Morimoto, Peter Wieghofer, Yuka Okada, Yuki Mori, Saburo Sakoda, Shizuya Saika, Yoshichika Yoshioka, Issei Komuro, Toshihide Yamashita, Toshio Hirano, Marco Prinz, Masaaki Murakami
ELIFE, 4, Aug. 2015, [Peer-reviewed]
English, Scientific journal - KDEL receptor 1 regulates T-cell homeostasis via PP1 that is a key phosphatase for ISR
Daisuke Kamimura, Kokichi Katsunuma, Yasunobu Arima, Toru Atsumi, Jing-jing Jiang, Hidenori Bando, Jie Meng, Lavannya Sabharwal, Andrea Stofkova, Naoki Nishikawa, Hironao Suzuki, Hideki Ogura, Naoko Ueda, Mineko Tsuruoka, Masaya Harada, Junya Kobayashi, Takanori Hasegawa, Hisahiro Yoshida, Haruhiko Koseki, Ikuo Miura, Shigeharu Wakana, Keigo Nishida, Hidemitsu Kitamura, Toshiyuki Fukada, Toshio Hirano, Masaaki Murakami
NATURE COMMUNICATIONS, 6, 7474, Jun. 2015, [Peer-reviewed]
English, Scientific journal - Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension
Takahiro Hashimoto-Kataoka, Naoki Hosen, Takashi Sonobe, Yoh Arita, Taku Yasui, Takeshi Masaki, Masato Minami, Tadakatsu Inagaki, Shigeru Miyagawa, Yoshiki Sawa, Masaaki Murakami, Atsushi Kumanogoh, Keiko Yamauchi-Takihara, Meinoshin Okumura, Tadamitsu Kishimoto, Issei Komuro, Mikiyasu Shirai, Yasushi Sakata, Yoshikazu Nakaoka
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 112, 20, E2677, E2686, May 2015, [Peer-reviewed]
English, Scientific journal - [Gateway Reflex, a regulator of the inflammation feedback loop by regional neural activation].
Arima Y, Kamimura D, Atsumi T, Murakami M
Nihon rinsho. Japanese journal of clinical medicine, 73, 4, 693, 700, 日本臨床社, Apr. 2015, [Peer-reviewed]
Japanese - Temporal Expression of Growth Factors Triggered by Epiregulin Regulates Inflammation Development
Masaya Harada, Daisuke Kamimura, Yasunobu Arima, Hitoshi Kohsaka, Yuji Nakatsuji, Makoto Nishida, Toru Atsumi, Jie Meng, Hidenori Bando, Rajeev Singh, Lavannya Sabharwal, Jing-Jing Jiang, Noriko Kumai, Nobuyuki Miyasaka, Saburo Sakoda, Keiko Yamauchi-Takihara, Hideki Ogura, Toshio Hirano, Masaaki Murakami
JOURNAL OF IMMUNOLOGY, 194, 3, 1039, 1046, Feb. 2015, [Peer-reviewed]
English, Scientific journal - Regulation of Inflammation Responses by Neural Activation
Murakami Masaaki
Shinzo, 47, 2, 261, 268, Japan Heart Foundation, 2015
Japanese - Role of cytokine-mediated crosstalk between T cells and nonimmune cells in the pathophysiology of multiple sclerosis
Daisuke Kamimura, Yasunobu Arima, Toru Atsumi, Jie Meng, Lavannya Sabharwal, Hidenori Bando, Hideki Ogura, Jing-Jing Jiang, Eric S. Huseby, Masaaki Murakami
Multiple Sclerosis: A Mechanistic View, 101, 125, Elsevier Inc., 01 Jan. 2015, [Peer-reviewed]
English, In book - Role of Inflammation Amplifier-Induced Growth Factor Expression in the Development of Inflammatory Diseases
Ikuma Nakagawa, Daisuke Kamimura, Toru Atsumi, Yasunobu Arima, Masaaki Murakami
CRITICAL REVIEWS IN IMMUNOLOGY, 35, 5, 365, 378, 2015, [Peer-reviewed]
English, Scientific journal - The Gateway Reflex, which is mediated by the inflammation amplifier, directs pathogenic immune cells into the CNS
Lavannya Sabharwal, Daisuke Kamimura, Jie Meng, Hidenori Bando, Hideki Ogura, Chiemi Nakayama, Jing-Jing Jiang, Noriko Kumai, Hironao Suzuki, Toru Atsumi, Yasunobu Arima, Masaaki Murakami
JOURNAL OF BIOCHEMISTRY, 156, 6, 299, 304, Dec. 2014, [Peer-reviewed]
English - Zinc transporter SLC39A10/ZIP10 controls humoral immunity by modulating B-cell receptor signal strength
Shintaro Hojyo, Tomohiro Miyai, Hitomi Fujishiro, Masami Kawamura, Takuwa Yasuda, Atsushi Hijikata, Bum-Ho Bin, Tarou Irie, Junichi Tanaka, Toru Atsumi, Masaaki Murakami, Manabu Nakayama, Osamu Ohara, Seiichiro Himeno, Hisahiro Yoshida, Haruhiko Koseki, Tomokatsu Ikawa, Kenji Mishima, Toshiyuki Fukada
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 111, 32, 11786, 11791, Aug. 2014, [Peer-reviewed]
English, Scientific journal - Temporal Changes in Lower-Lumbar Spinal Cord in EAE Mouse
Mori Y, Murakami M, Arima Y, Zhu D, Yoshioka Y
Japanese J Magn Reson Med, 34, 3, 96, 99, Aug. 2014, [Peer-reviewed]
Japanese, Scientific journal - CD4⁺ T cell cytokine gene and protein expression in duodenal mucosa of dogs with inflammatory bowel disease.
Hiroshi Ohta, Kanae Takada, Yuji Sunden, Yu Tamura, Tatsuyuki Osuga, Sue Yee Lim, Masahiro Murakami, Noboru Sasaki, Bandula Kumara Wickramasekara Rajapakshage, Kensuke Nakamura, Masahiro Yamasaki, Mitsuyoshi Takiguchi
The Journal of veterinary medical science, 76, 3, 409, 14, Mar. 2014, [Peer-reviewed], [Domestic magazines]
English, Scientific journal - The Reverse-Direction Method Links Mass Experimental Data to Human Diseases
Hideki Ogura, Toru Atsumi, Hidenori Bando, Lavannya Sabharwal, Moe Yamada, Jing-Jing Jiang, Akihiro Nakamura, Yasunobu Arima, Daisuke Kamimura, Masaaki Murakami
ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS, 62, 1, 41, 45, Feb. 2014, [Peer-reviewed]
English - Early pathological alterations of lower lumbar cords detected by ultrahigh-field MRI in a mouse multiple sclerosis model
Yuki Mori, Masaaki Murakami, Yasunobu Arima, Dasong Zhu, Yasuo Terayama, Yutaka Komai, Yuji Nakatsuji, Daisuke Kamimura, Yoshichika Yoshioka
INTERNATIONAL IMMUNOLOGY, 26, 2, 93, 101, Feb. 2014, [Peer-reviewed]
English, Scientific journal - Inflammation Amplifier, a New Paradigm in Cancer Biology
Toru Atsumi, Rajeev Singh, Lavannya Sabharwal, Hidenori Bando, Jie Meng, Yasunobu Arima, Moe Yamada, Masaya Harada, Jing-Jing Jiang, Daisuke Kamimura, Hideki Ogura, Toshio Hirano, Masaaki Murakami
CANCER RESEARCH, 74, 1, 8, 14, Jan. 2014, [Peer-reviewed]
English - IL-6 and inflammatory diseases
Daisuke Kamimura, Yasunobu Arima, Toshio Hirano, Hideki Ogura, Masaaki Murakami
Cytokine Frontiers: Regulation of Immune Responses in Health and Disease, 53, 78, Springer Japan, 01 Jan. 2014, [Peer-reviewed]
English, In book - Qualitative and Quantitative Contrast Enhanced Ultrasonography of the Pancreas Using Bolus Injection and Continuous Infusion Methods in Normal Dogs
Sue Yee Lim, Kensuke Nakamura, Keitaro Morishita, Noboru Sasaki, Masahiro Murakami, Tatsuyuki Osuga, Hiroshi Ohta, Masahiro Yamasaki, Mitsuyoshi Takiguchi
JOURNAL OF VETERINARY MEDICAL SCIENCE, 75, 12, 1601, 1607, Dec. 2013, [Peer-reviewed]
English, Scientific journal - Markedly increased expression of interleukin-8 in the colorectal mucosa of inflammatory colorectal polyps in miniature dachshunds
Yu Tamura, Hiroshi Ohta, Shidow Torisu, Masashi Yuki, Nozomu Yokoyama, Masahiro Murakami, Sue Yee Lim, Tatsuyuki Osuga, Keitaro Morishita, Kensuke Nakamura, Masahiro Yamasaki, Mitsuyoshi Takiguchi
VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY, 156, 1-2, 32, 42, Nov. 2013, [Peer-reviewed]
English, Scientific journal - Short-term Outcome of Hypofractionated Three-dimensional Conformal Radiation Therapy for Pituitary Tumors in Doge
MORI Takashi, ITO Yusuke, YAMAZAKI Mifumi, MURAKAMI Mami, NOGUCHI Shunsuke, YAMADA Nami, MARUO Kohji
Journal of the Japan Veterinary Medical Association, 66, 10, 709, 712, Japan Veterinary Medical Association, 20 Oct. 2013
Japanese, Fifteen dogs with pituitary tumors were treated with a weekly schedule of hypofractionated three-dimensional conformal radiation therapy (3D-CRT). The median total dose was 48 Gy (range: 35-52 Gy), with a median irradiation dose/fraction of 7 Gy (5-8 Gy). The median follow-up time was 298 days. Twelve dogs were alive at the time of analysis. One dog died before completing the course of radiation therapy. Two died at 372 and 479 days after 3D-CRT. Although six of the 13 dogs with pituitary-dependent hyperadrenocorticism had improvement of clinical signs, none were able to stop receiving trilostane. Of the 13 dogs with neurologic signs, 10 had complete resolution and three had partial resolution. None of the dogs developed acute or late adverse effects due to 3D-CRT. Our preliminary results suggest that hypofractionated 3D-CRT was feasible in dogs with pituitary tumors. - Expression of CD4(+) T cell cytokine genes in the colorectal mucosa of inflammatory colorectal polyps in miniature dachshunds
Hiroshi Ohta, Kanae Takada, Shidow Torisu, Masashi Yuki, Yu Tamura, Nozomu Yokoyama, Tatsuyuki Osuga, Sue Yee Lim, Masahiro Murakami, Noboru Sasaki, Kensuke Nakamura, Masahiro Yamasaki, Mitsuyoshi Takiguchi
VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY, 155, 4, 259, 263, Oct. 2013, [Peer-reviewed]
English, Scientific journal - Adaptive-servo ventilation combined with deep sedation is an effective strategy during pulmonary vein isolation
Takashi Murakami, Hirosuke Yamaji, Kenji Numa, Hiroshi Kawamura, Masaaki Murakami, Shunichi Higashiya, Shigeshi Kamikawa, Kazuyoshi Hina, Satoshi Hirohata, Shozo Kusachi
Europace, 15, 7, 951, 956, Jul. 2013, [Peer-reviewed]
English, Scientific journal - Repeatability and reproducibility of measurements obtained via two-dimensional speckle tracking echocardiography of the left atrium and time-left atrial area curve analysis in healthy dogs
Tatsuyuki Osuga, Kensuke Nakamura, Sue Yee Lim, Yu Tamura, Wickramasekara Rajapakshage Bandula Kumara, Masahiro Murakami, Noboru Sasaki, Keitaro Morishita, Hiroshi Ohta, Masahiro Yamasaki, Mitsuyoshi Takiguchi
AMERICAN JOURNAL OF VETERINARY RESEARCH, 74, 6, 864, 869, Jun. 2013, [Peer-reviewed]
English, Scientific journal - Usefulness of dabigatran etexilate as periprocedural anticoagulation therapy for atrial fibrillation ablation
Hirosuke Yamaji, Takashi Murakami, Kazuyoshi Hina, Shunichi Higashiya, Hiroshi Kawamura, Masaaki Murakami, Shigeshi Kamikawa, Satoshi Hirohata, Shozo Kusachi
Clinical Drug Investigation, 33, 6, 409, 418, Jun. 2013, [Peer-reviewed]
English, Scientific journal - Commensal microbe-derived butyrate induces colonic regulatory T cells.
Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, Takahashi M, Fukuda NR, Murakami M, Miyauchi E, Hino S, Atarashi K, Onawa S, Fujimura Y, Lockett T, Clarke JM, Topping DL, Tomita M, Hori S, Ohara O, Morita T, Koseki H, Kikuchi J, Honda K, Hase K, Ohno H
Nature, 500, 232-236, Jun. 2013, [Peer-reviewed]
English, Scientific journal - Erratum to Disease-Association Analysis of an Inflammation-Related Feedback Loop [Cell Reports 3, (2013) 946-959]
Masaaki Murakami, Masaya Harada, Daisuke Kamimura, Hideki Ogura, Yuko Okuyama, Noriko Kumai, Azusa Okuyama, Rajeev Singh, Jing-Jing Jiang, Toru Atsumi, Sayaka Shiraya, Yuji Nakatsuji, Makoto Kinoshita, Hitoshi Kohsaka, Makoto Nishida, Saburo Sakoda, Nobuyuki Miyasaka, Keiko Yamauchi-Takihara, Toshio Hirano
Cell Reports, 3, 5, 1754, 30 May 2013, [Peer-reviewed]
English, Scientific journal - IL-6 amplifier activation in epithelial regions of bronchi after allogeneic lung transplantation
Jihye Lee, Tomoyuki Nakagiri, Daisuke Kamimura, Masaya Harada, Takahiro Oto, Yoshiyuki Susaki, Yasushi Shintani, Masayoshi Inoue, Shinichiro Miyoshi, Eiichi Morii, Toshio Hirano, Masaaki Murakami, Meinoshin Okumura
INTERNATIONAL IMMUNOLOGY, 25, 5, 319, 332, May 2013, [Peer-reviewed]
English, Scientific journal - Disease-association analysis of an inflammation-related feedback loop.
Masaaki Murakami, Masaya Harada, Daisuke Kamimura, Hideki Ogura, Yuko Okuyama, Noriko Kumai, Azusa Okuyama, Rajeev Singh, Jing-Jing Jiang, Toru Atsumi, Sayaka Shiraya, Yuji Nakatsuji, Makoto Kinoshita, Hitoshi Kohsaka, Makoto Nishida, Saburo Sakoda, Nobuyuki Miyasaka, Keiko Yamauchi-Takihara, Toshio Hirano
Cell reports, 3, 3, 946, 59, 3, 28 Mar. 2013, [Peer-reviewed], [International Magazine]
English, Scientific journal, The IL-6-triggered positive feedback loop for NFκB signaling (or the IL-6 amplifier/Inflammation amplifier) was originally discovered as a synergistic-activation signal that follows IL-17/IL-6 stimulation in nonimmune cells. Subsequent results from animal models have shown that the amplifier is activated by stimulation of NFκB and STAT3 and induces chemokines and inflammation via an NFκB loop. However, its role in human diseases is unclear. Here, we combined two genome-wide mouse screens with SNP-based disease association studies, revealing 1,700 genes related to the IL-6 amplifier, 202 of which showed 492 indications of association with ailments beyond autoimmune diseases. We followed up on ErbB1 from our list. Blocking ErbB1 signaling suppressed the IL-6 amplifier, whereas the expression of epiregulin, an ErbB1 ligand, was higher in patients with inflammatory diseases. These results indicate that the IL-6 amplifier is indeed associated with human diseases and disorders and that the identified genes may make for potential therapeutic targets. - Autoimmune disorder phenotypes in Hvcn1-deficient mice
Mari Sasaki, Akihiro Tojo, Yoshifumi Okochi, Nana Miyawaki, Daisuke Kamimura, Akihito Yamaguchi, Masaaki Murakami, Yasushi Okamura
BIOCHEMICAL JOURNAL, 450, 295, 301, Mar. 2013, [Peer-reviewed]
English, Scientific journal - Ecto-Nucleoside Triphosphate Diphosphohydrolase 7 Controls Th17 Cell Responses through Regulation of Luminal ATP in the Small Intestine
Takashi Kusu, Hisako Kayama, Makoto Kinoshita, Seong Gyu Jeon, Yoshiyasu Ueda, Yoshiyuki Goto, Ryu Okumura, Hiroyuki Saiga, Takashi Kurakawa, Kayo Ikeda, Yuichi Maeda, Jun-ichi Nishimura, Yasunobu Arima, Koji Atarashi, Kenya Honda, Masaaki Murakami, Jun Kunisawa, Hiroshi Kiyono, Meinoshin Okumura, Masahiro Yamamoto, Kiyoshi Takeda
JOURNAL OF IMMUNOLOGY, 190, 2, 774, 783, Jan. 2013, [Peer-reviewed]
English, Scientific journal - Regulation of immune cell infiltration into the CNS by regional neural inputs explained by the gate theory
Yasunobu Arima, Daisuke Kamimura, Lavannya Sabharwal, Moe Yamada, Hidenori Bando, Hideki Ogura, Toru Atsumi, Masaaki Murakami
Mediators of Inflammation, 2013, 898165, 2013, [Peer-reviewed]
English - The gateway theory: Bridging neural and immune interactions in the CNS
Daisuke Kamimura, Moe Yamada, Masaya Harada, Lavannya Sabharwal, Jie Meng, Hidenori Bando, Hideki Ogura, Toru Atsumi, Yasunobu Arima, Masaaki Murakami
Frontiers in Neuroscience, 7, 7, 204, 2013, [Peer-reviewed]
English, Scientific journal - The gateway theory: How regional neural activation creates a gateway for immune cells via an inflammation amplifier
Hideki Ogura, Yasunobu Arima, Daisuke Kamimura, Masaaki Murakami
Biomedical Journal, 36, 6, 269, 273, 6, 2013, [Peer-reviewed]
English - Outcome of chemoradiotherapy using orthovoltage X-ray for canine intranasal tumors.
Yanase S, Mori T, Hoshino Y, Ito Y, Murakami M, Nishitani Y, Noguchi S, Sakai H, Yanai T, Maruo K
Jpn J Vet Anesth Surg, 43, 3&4, 41, 45, Japanese Society of Veterinary Anesthesia & Surgery, 2013
Japanese, We retrospectively reviewed 11 canine cases of malignant intranasal tumors treated with chemoradiotherapy. All the dogs received orthovoltage radiation in weekly 6.3 Gy fractions and multi-agent chemotherapy containing doxorubicin and carboplatin. The dogs were irradiated 4-11 times; the total dose of irradiation was 25.2-69.3 Gy. The median irradiation dose was 37.8 Gy. Clinical symptoms improved in 9 cases. Computed tomography (CT) images taken before and after treatment showed tumor regression in 8 cases; complete remission was achieved in 2 dogs and partial remission in 6. The median survival time was 478 days (99-969 days). Although adverse effects of radiation were observed in 7 cases, the symptoms were mild and improved with symptomatic treatment. In conclusion, our retrospective study suggests that chemoradiotherapy using orthovoltage might be effective for managing canine malignant intranasal tumors and for prolonging the survival period without affecting the quality of life. - [IL-6 signal transduction and its physiological roles].
Murakami M, Arima Y, Hirano T
Nihon rinsho. Japanese journal of clinical medicine, 70 Suppl 8, 192, 206, Nov. 2012, [Peer-reviewed] - サイトカインとケモカイン-1 MTF-1の新たな標的遺伝子であるmolecular-XはNF-κB活性化を介してIL-6アンプ活性化を制御する(Molecular-X, which is a novel MTF-1 target gene regulates the IL-6 amplifier activation via NF κB activation)
Otsubo Ryota, Okuyama Yuko, Andrews Glen K., Hirano Toshio, Murakami Masaaki
日本免疫学会総会・学術集会記録, 41, 65, 65, (NPO)日本免疫学会, Nov. 2012
English - Involvement of Mitochondrial Genes of Babesia gibsoni in Resistance to Diminazene Aceturate
Bandula Kumara Wickramasekara Rajapakshage, Masahiro Yamasaki, Shiang-Jyi Hwang, Noboru Sasaki, Masahiro Murakami, Yu Tamura, Sue Yee Lim, Kensuke Nakamura, Hiroshi Ohta, Mitsuyoshi Takiguchi
JOURNAL OF VETERINARY MEDICAL SCIENCE, 74, 9, 1139, 1148, Sep. 2012, [Peer-reviewed]
English, Scientific journal - IL-6 Amplifier, NF-kappa B-Triggered Positive Feedback for IL-6 Signaling, in Grafts Is Involved in Allogeneic Rejection Responses
Jihye Lee, Tomoyuki Nakagiri, Takahiro Oto, Masaya Harada, Eiichi Morii, Yasushi Shintani, Masayoshi Inoue, Yoichiro Iwakura, Shinichiro Miyoshi, Meinoshin Okumura, Toshio Hirano, Masaaki Murakami
JOURNAL OF IMMUNOLOGY, 189, 4, 1928, 1936, Aug. 2012, [Peer-reviewed]
English, Scientific journal - Analysis of energy generation and glycolysis pathway in diminazene aceturate-resistant Babesia gibsoni isolate in vitro
Bandula Kumara Wickramasekara Rajapakshage, Masahiro Yamasaki, Masahiro Murakami, Yu Tamura, Sue Yee Lim, Tatsuyuki Osuga, Noboru Sasaki, Kensuke Nakamura, Hiroshi Ohta, Mitsuyoshi Takiguchi
JAPANESE JOURNAL OF VETERINARY RESEARCH, 60, 2-3, 51, 61, Aug. 2012, [Peer-reviewed]
English, Scientific journal - Intestinal CX3C chemokine receptor 1(high) (CX(3)CR1(high)) myeloid cells prevent T-cell-dependent colitis
Hisako Kayama, Yoshiyasu Ueda, Yukihisa Sawa, Seong Gyu Jeon, Ji Su Ma, Ryu Okumura, Atsuko Kubo, Masaru Ishii, Taku Okazaki, Masaaki Murakami, Masahiro Yamamoto, Hideo Yagita, Kiyoshi Takeda
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 109, 13, 5010, 5015, Mar. 2012, [Peer-reviewed]
English, Scientific journal - Regional Neural Activation Defines a Gateway for Autoreactive T Cells to Cross the Blood-Brain Barrier
Yasunobu Arima, Masaya Harada, Daisuke Kamimura, Jin-Haeng Park, Fuminori Kawano, Fiona E. Yull, Tadafumi Kawamoto, Yoichiro Iwakura, Ulrich A. K. Betz, Gabriel Marquez, Timothy S. Blackwell, Yoshinobu Ohira, Toshio Hirano, Masaaki Murakami
CELL, 148, 3, 447, 457, Feb. 2012, [Peer-reviewed]
English, Scientific journal - The Pathological and Physiological Roles of IL-6 Amplifier Activation
Masaaki Murakami, Toshio Hirano
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES, 8, 9, 1267, 1280, 2012, [Peer-reviewed]
English - The molecular mechanisms of chronic inflammation development
Masaaki Murakami, Toshio Hirano
FRONTIERS IN IMMUNOLOGY, 3, 323, 2012, [Peer-reviewed]
English - ACTIVATION OF MICROBUBBLES BY SHORT-PULSED ULTRASOUND ENHANCES THE CYTOTOXIC EFFECT OF CIS-DIAMMINEDICHLOROPLATINUM (II) IN A CANINE THYROID ADENOCARCINOMA CELL LINE IN VITRO
Noboru Sasaki, Nobuki Kudo, Kensuke Nakamura, Sue Yee Lim, Masahiro Murakami, W. R. Bandula Kumara, Yu Tamura, Hiroshi Ohta, Masahiro Yamasaki, Mitsuyoshi Takiguchi
ULTRASOUND IN MEDICINE AND BIOLOGY, 38, 1, 109, 118, Jan. 2012, [Peer-reviewed]
English, Scientific journal - Sufficient pulmonary vein image quality of non-enhanced multi-detector row computed tomography for pulmonary vein isolation by catheter ablation
Hirosuke Yamaji, Kazuyoshi Hina, Hiroshi Kawamura, Takashi Murakami, Masaaki Murakami, Satoshi Hirohata, Natsuki Ohmaru, Shozo Kusachi
Europace, 14, 1, 52, 59, Jan. 2012, [Peer-reviewed]
English, Scientific journal - Inguinal skin window for chronic two-photon In vivo imaging of mouse lymph node
Yutaka Komai, Punniyakoti Thanikachalam Veeraveedu, Daisuke Kamimura, Masaaki Murakami
2012 WORLD AUTOMATION CONGRESS (WAC), 2012, [Peer-reviewed]
English, International conference proceedings - Effects and Mechanisms of Action of Polyene Macrolide Antibiotic Nystatin on Babesia gibsoni In Vitro
Masahiro Yamasaki, Norihisa Tamura, Kensuke Nakamura, Noboru Sasaki, Masahiro Murakami, Wickramasekara Rajapakshage, Bandula Kumara, Yu Tamura, Sue Yee Lim, Hiroshi Ohta, Mitsuyoshi Takiguchi
JOURNAL OF PARASITOLOGY, 97, 6, 1190, 1192, Dec. 2011, [Peer-reviewed]
English, Scientific journal - サイトカイン・ケモカイン 新しい生理機能 MTF-1標的分子がIL-6アンプの活性化を制御する(A MTF-1 target, which regulates the IL-6 amplifier activation)
大坪 亮太, 奥山 祐子, Andrews Glen K., 平野 俊夫, 村上 正晃
日本免疫学会総会・学術集会記録, 40, 112, 112, (NPO)日本免疫学会, Nov. 2011
English - Zinc homeostasis and signaling in health and diseases
Toshiyuki Fukada, Satoru Yamasaki, Keigo Nishida, Masaaki Murakami, Toshio Hirano
JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY, 16, 7, 1123, 1134, Oct. 2011, [Peer-reviewed]
English - SIRP alpha/CD172a Regulates Eosinophil Homeostasis
Noel Verjan Garcia, Eiji Umemoto, Yasuyuki Saito, Mikako Yamasaki, Erina Hata, Takashi Matozaki, Masaaki Murakami, Yun-Jae Jung, So-Youn Woo, Ju-Young Seoh, Myoung Ho Jang, Katsuyuki Aozasa, Masayuki Miyasaka
JOURNAL OF IMMUNOLOGY, 187, 5, 2268, 2277, Sep. 2011, [Peer-reviewed]
English, Scientific journal - Expression and subcellular localization of apical junction proteins in canine duodenal and colonic mucosa
Hiroshi Ohta, Tomoki Yamaguchi, B. K. Wickramasekara Rajapakshage, Masahiro Murakami, Noboru Sasaki, Kensuke Nakamura, Shiang-Jyi Hwang, Masahiro Yamasaki, Mitsuyoshi Takiguchi
AMERICAN JOURNAL OF VETERINARY RESEARCH, 72, 8, 1046, 1051, Aug. 2011, [Peer-reviewed]
English, Scientific journal - Detection of anti-Babesia gibsoni heat shock protein 70 antibody and anti-canine heat shock protein 70 antibody in sera from Babesia gibsoni-infected dogs
Masahiro Yamasaki, Mikiko Ishida, Kensuke Nakamura, Noboru Sasaki, Masahiro Murakami, Wickramasekara Rajapakshage Bandula Kumara, Yu Tamura, Sue Yee Lim, Hiroshi Ohta, Mitsuyoshi Takiguchi
VETERINARY PARASITOLOGY, 180, 3-4, 215, 225, Aug. 2011, [Peer-reviewed]
English, Scientific journal - A four-step model for the IL-6 amplifier, a regulator of chronic inflammations in tissue-specific MHC class II-associated autoimmune diseases
Masaaki Murakami, Toshio Hirano
FRONTIERS IN IMMUNOLOGY, 2, 22, 2011, [Peer-reviewed]
English - Local microbleeding facilitates IL-6- and IL-17-dependent arthritis in the absence of tissue antigen recognition by activated T cells
Masaaki Murakami, Yuko Okuyama, Hideki Ogura, Shogo Asano, Yasunobu Arima, Mineko Tsuruoka, Masaya Harada, Minoru Kanamoto, Yukihisa Sawa, Yoichiro Iwakura, Kiyoshi Takatsu, Daisuke Kamimura, Toshio Hirano
JOURNAL OF EXPERIMENTAL MEDICINE, 208, 1, 103, 114, Jan. 2011, [Peer-reviewed]
English, Scientific journal - Babesia gibsoni: Detection in blood smears and formalin-fixed, paraffin-embedded tissues using deoxyribonucleic acid in situ hybridization analysis
Masahiro Yamasaki, Yusuke Kobayashi, Kensuke Nakamura, Noboru Sasaki, Masahiro Murakami, Bandula Kumara Wickramasekara Rajapakshage, Hiroshi Ohta, Osamu Yamato, Yoshimitsu Maede, Mitsuyoshi Takiguchi
EXPERIMENTAL PARASITOLOGY, 127, 1, 119, 126, Jan. 2011, [Peer-reviewed]
English, Scientific journal - Reduced transcript levels of the heat shock protein 70 gene in diminazene aceturate-resistant Babesia gibsoni variants under low concentrations of diminazene aceturate
Shiang-Jyi Hwang, Masahiro Yamasaki, Kensuke Nakamura, Noboru Sasaki, Masahiro Murakami, Bandula Kumara Wickramasekara Rajapakshage, Hiroshi Ohta, Yoshimitsu Maede, Mitsuyoshi Takiguchi
JAPANESE JOURNAL OF VETERINARY RESEARCH, 58, 3-4, 155, 164, Nov. 2010, [Peer-reviewed]
English, Scientific journal - Development and Characterization of a Strain of Babesia gibsoni Resistant to Diminazene Aceturate In Vitro
Shiang-Jyi Hwang, Masahiro Yamasaki, Kensuke Nakamura, Noboru Sasaki, Masahiro Murakami, Bandula Kumara Wickramasekara Rajapakshage, Hiroshi Ohta, Yoshimitsu Maede, Mitsuyoshi Takiguchi
JOURNAL OF VETERINARY MEDICAL SCIENCE, 72, 6, 765, 771, Jun. 2010, [Peer-reviewed]
English, Scientific journal - Zinc suppresses T(h)17 development via inhibition of STAT3 activation
Chika Kitabayashi, Toshiyuki Fukada, Minoru Kanamoto, Wakana Ohashi, Shintaro Hojyo, Toru Atsumi, Naoko Ueda, Ichiro Azuma, Hiroshi Hirota, Masaaki Murakami, Toshio Hirano
INTERNATIONAL IMMUNOLOGY, 22, 5, 375, 386, May 2010, [Peer-reviewed]
English, Scientific journal - Impact of Olmesartan on Progression of Coronary Atherosclerosis. A Serial Volumetric Intravascular Ultrasound Analysis From the OLIVUS (Impact of OLmesarten on progression of coronary atherosclerosis: evaluation by IntraVascular UltraSound) Trial
Atsushi Hirohata, Keizo Yamamoto, Toru Miyoshi, Kunihiko Hatanaka, Satoshi Hirohata, Hitoshi Yamawaki, Issei Komatsubara, Masaaki Murakami, Eiki Hirose, Shinji Sato, Keisuke Ohkawa, Makoto Ishizawa, Hirosuke Yamaji, Hiroshi Kawamura, Shozo Kusachi, Takashi Murakami, Kazuyoshi Hina, Tohru Ohe
Journal of the American College of Cardiology, 55, 10, 976, 982, 09 Mar. 2010, [Peer-reviewed]
English, Scientific journal - IL-6 positively regulates Foxp3(+)CD8(+) T cells in vivo
Takayuki Nakagawa, Mineko Tsuruoka, Hideki Ogura, Yuko Okuyama, Yasunobu Arima, Toshio Hirano, Masaaki Murakami
INTERNATIONAL IMMUNOLOGY, 22, 2, 129, 139, Feb. 2010, [Peer-reviewed]
English, Scientific journal - CONTRAST-ENHANCED ULTRASONOGRAPHY FOR CHARACTERIZATION OF CANINE FOCAL LIVER LESIONS
Kensuke Nakamura, Satoshi Takagi, Noboru Sasaki, Wickramasekara Rajapakshage Bandula Kumara, Masahiro Murakami, Hiroshi Ohta, Masahiro Yamasaki, Mitsuyoshi Takiguchi
VETERINARY RADIOLOGY & ULTRASOUND, 51, 1, 79, 85, Jan. 2010, [Peer-reviewed]
English, Scientific journal - Primary Splenic Torsion in a Boston Terrier
Hiroshi Ohta, Satoshi Takagi, Masahiro Murakami, Noboru Sasaki, Muneyoshi Yoshikawa, Kensuke Nakamura, Shiang-Jyi Hwang, Masahiro Yamasaki, Mitsuyoshi Takiguchi
JOURNAL OF VETERINARY MEDICAL SCIENCE, 71, 11, 1533, 1535, Nov. 2009, [Peer-reviewed]
English, Scientific journal - Hepatic Interleukin-7 Expression Regulates T Cell Responses
Yukihisa Sawa, Yasunobu Arima, Hideki Ogura, Chika Kitabayashi, Jing-Jing Jiang, Toru Fukushima, Daisuke Kamimura, Toshio Hirano, Masaaki Murakami
IMMUNITY, 30, 3, 447, 457, Mar. 2009, [Peer-reviewed]
English, Scientific journal - IFN-gamma expression in CD8(+) T cells regulated by IL-6 signal is involved in superantigen-mediated CD4(+) T cell death
Toru Atsumi, Masae Sato, Daisuke Kamimura, Arisa Moroi, Yoichiro Iwakura, Ulrich A. K. Betz, Akihiko Yoshimura, Mika Nishihara, Toshio Hirano, Masaaki Murakami
INTERNATIONAL IMMUNOLOGY, 21, 1, 73, 80, Jan. 2009, [Peer-reviewed]
English, Scientific journal - Successful cisplatin chemotherapy and radiotherapy in a dog with ovarian dysgerminoma.
Nakayama M, Mori T, Iwatani N, Sakai H, Murakami M, Sato A, Maruo K
J Jpn Vet Med Assoc, 62, 5, 395, 397, 2009 - 【樹状細胞による免疫制御と臨床応用 T細胞制御機構の理解から、樹状細胞療法の開発、自己免疫疾患・感染症の病態解明とその治療まで】樹状細胞の生物学と生理学(分化・サブセット活性化・動態) 樹状細胞による抗原提示の制御機構
北條 慎太郎, 村上 正晃
実験医学, 26, 20, 3158, 3168, (株)羊土社, Dec. 2008
Japanese - Interleukin-17 Promotes Autoimmunity by Triggering a Positive-Feedback Loop via Interleukin-6 Induction
Hideki Ogura, Masaaki Murakami, Yuko Okuyama, Mineko Tsuruoka, Chika Kitabayashi, Minoru Kanamoto, Mika Nishihara, Yoichiro Iwakura, Toshio Hirano
IMMUNITY, 29, 4, 628, 636, Oct. 2008, [Peer-reviewed]
English, Scientific journal - c-Cbl-dependent monoubiquitination and lysosomal degradation of gp130
Yoshinori Tanaka, Nobuyuki Tanaka, Yasushi Saeki, Keiji Tanaka, Masaaki Murakami, Toshio Hirano, Naoto Ishii, Kazuo Sugamura
MOLECULAR AND CELLULAR BIOLOGY, 28, 15, 4805, 4818, Aug. 2008, [Peer-reviewed]
English, Scientific journal - Intracellular zinc homeostasis and zinc signaling
Masaaki Murakami, Toshio Hirano
CANCER SCIENCE, 99, 8, 1515, 1522, Aug. 2008, [Peer-reviewed]
English - Combination treatment with IL-2 and anti-IL-2 mAbs reduces tumor metastasis via NK cell activation
Gui-Hua Jin, Toshio Hirano, Masaaki Murakami
INTERNATIONAL IMMUNOLOGY, 20, 6, 783, 789, Jun. 2008, [Peer-reviewed]
English, Scientific journal - Higher incidence and serum levels of minor cardiac biomarker elevation in sirolimus-eluting stent (Cypher) than bare metal stent implantations
Tetsushi Seitou, Masaaki Murakami, Issei Komatsubara, Hiroshi Kawamura, Keizo Yamamoto, Kazuyoshi Hina, Satoshi Hirohata, Ryoko Shinohata, Yoshifumi Ninomiya, Shozo Kusachi
Coronary Artery Disease, 19, 2, 63, 69, Mar. 2008, [Peer-reviewed]
English, Scientific journal - Roles of zinc and zinc signaling in immunity: Zinc as an intracellular signaling molecule
Toshio Hirano, Masaaki Murakami, Toshiyuki Fukada, Keigo Nishida, Satoru Yamasaki, Tomoyuki Suzuki
ADVANCES IN IMMUNOLOGY, VOL 97, 97, 149, 176, 2008, [Peer-reviewed]
English, In book - Association of corrected QT dispersion with symptoms improvement in patients receiving cardiac resynchronization therapy
Kazuyoshi Hina, Hiroshi Kawamura, Takashi Murakami, Keizo Yamamoto, Hirosuke Yamaji, Masaaki Murakami, Satoshi Hirohata, Hiroko Ogawa, Kohsuke Sakane, Shozo Kusachi
Heart and Vessels, 23, 5, 325, 333, 2008, [Peer-reviewed]
English, Scientific journal - Prone position is essential for detection of pulmonary vein pseudostenosis by enhanced multidetector computed tomography in patients who undergo pulmonary vein isolation
Hirosuke Yamaji, Kazuyoshi Hina, Hiroshi Kawamura, Takashi Murakami, Masaaki Murakami, Keizo Yamamoto, Atsushi Hirohata, Toru Miyoshi, Satoshi Hirohata, Shozo Kusachi
Circulation Journal, 72, 9, 1460, 1464, 2008, [Peer-reviewed]
English, Scientific journal - 基礎医学から 免疫機構における亜鉛の役割
深田 俊幸, 山崎 哲, 北條 慎太郎, 西田 圭吾, 村上 正晃, 平野 俊夫
日本医事新報, 4343, 63, 69, (株)日本医事新報社, Jul. 2007
Japanese - IL-6-gp130-STAT3 in T cells directs the development of IL-17+T-h with a minimum effect on that of Treg in the steady state
Mika Nishihara, Hideki Ogura, Naoko Ueda, Mineko Tsuruoka, Chika Kitabayashi, Fumio Tsuji, Hiroyuki Aono, Katsuhiko Ishihara, Eric Huseby, Ulrich A. K. Betz, Masaaki Murakami, Toshio Hirano
INTERNATIONAL IMMUNOLOGY, 19, 6, 695, 702, Jun. 2007, [Peer-reviewed]
English, Scientific journal - Homeostatically proliferating CD4(+) T cells are involved in the pathogenesis of an Omenn syndrome murine model
Khie Khiong, Masaaki Murakami, Chika Kitabayashi, Naoko Ueda, Shin-ichiro Sawa, Akemi Sakamoto, Brian L. Kotzin, Stephen J. Rozzo, Katsuhiko Ishihara, Marileila Verella-Garcia, John Kappler, Philippa Marrack, Toshio Hirano
JOURNAL OF CLINICAL INVESTIGATION, 117, 5, 1270, 1281, May 2007, [Peer-reviewed]
English, Scientific journal - Homeostatically proliferating CD4+ T cells are involved in the pathogenesis of an Omenn syndrome murine model
Khie Khiong, Masaaki Murakami, Chika Kitabayashi, Naoko Ueda, Shin-Ichiro Sawa, Akemi Sakamoto, Brian L. Kotzin, Stephen J. Rozzo, Katsuhiko Ishihara, Marileila Verella-Garcia, John Kappler, Philippa Marrack, Toshio Hirano
Journal of Clinical Investigation, 117, 5, 1270, 1281, 01 May 2007, [Peer-reviewed]
English, Scientific journal - Toll-like receptor-mediated regulation of zinc homeostasis influences dendritic cell function
Hidemitsu Kitamura, Hideyuki Morikawa, Hokuto Kamon, Megumi Iguchi, Shintaro Hojyo, Toshiyuki Fukada, Susumu Yamashita, Tsuneyasu Kaisho, Shizuo Akira, Masaaki Murakami, Toshio Hirano
NATURE IMMUNOLOGY, 7, 9, 971, 977, Sep. 2006, [Peer-reviewed]
English, Scientific journal - CD1d-restricted NKT cell activation enhanced homeostatic proliferation of CD8(+) T cells in a manner dependent on IL-4
Naoko Ueda, Hiroko Kuki, Daisuke Kamimura, Shinichiro Sawa, Kenichiro Seino, Takuya Tashiro, Ken-ichi Fushuku, Masaru Taniguchi, Toshio Hirano, Masaaki Murakami
INTERNATIONAL IMMUNOLOGY, 18, 9, 1397, 1404, Sep. 2006, [Peer-reviewed]
English, Scientific journal - TRIF-GEFH1-RhoB pathway is involved in MHCII expression on dendritic cells that is critical for CD4 T-cell activation
Hokuto Kamon, Takaya Kawabe, Hidemitsu Kitamura, Jihye Lee, Daisuke Kamimura, Tsuneyasu Kaisho, Shizuo Akira, Akihiro Iwamatsu, Hisashi Koga, Masaaki Murakami, Toshio Hirano
EMBO JOURNAL, 25, 17, 4108, 4119, Sep. 2006, [Peer-reviewed]
English, Scientific journal - Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocytes/macrophages
Masato Murakami, Shinobu Iwai, Sachie Hiratsuka, Mai Yamauchi, Kazuhide Nakamura, Yoichiro Iwakura, Masabumi Shibuya
BLOOD, 108, 6, 1849, 1856, Sep. 2006, [Peer-reviewed]
English, Scientific journal - IL-2 in vivo activities and antitumor efficacy enhanced by an anti-IL-2 mAb
D Kamimura, Y Sawa, M Sato, E Agung, T Hirano, M Murakami
JOURNAL OF IMMUNOLOGY, 177, 1, 306, 314, Jul. 2006, [Peer-reviewed]
English, Scientific journal - Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic proliferation of CD4(+) T cells
S Sawa, D Kamimura, GH Jin, H Morikawa, H Kamon, M Nishihara, K Ishihara, M Murakami, T Hirano
JOURNAL OF EXPERIMENTAL MEDICINE, 203, 6, 1459, 1470, Jun. 2006, [Peer-reviewed]
English, Scientific journal - Grasp a pTyr-peptide by its SOCS
T Hirano, M Murakami
DEVELOPMENTAL CELL, 10, 5, 542, 544, May 2006, [Peer-reviewed]
English - Coronary pressure measurement to identify the lesion requiring percutaneous coronary intervention in equivocal tandem lesions
Minoru Hirota, Kohichiro Iwasaki, Keizo Yamamoto, Shozo Kusachi, Kazuyoshi Hina, Satoshi Hirohata, Masaaki Murakami, Shigeshi Kamikawa, Takashi Murakami, Yasushi Shiratori
Coronary Artery Disease, 17, 2, 181, 186, Mar. 2006, [Peer-reviewed]
English, Scientific journal - Nicorandil reduces the incidence of minor cardiac marker elevation after coronary stenting
Masaaki Murakami, Kohichiro Iwasaki, Shozo Kusachi, Kazuyoshi Hina, Minoru Hirota, Satoshi Hirohata, Shigeshi Kamikawa, Mutsuko Sangawa, Keizo Yamamoto, Yasushi Shiratori
International Journal of Cardiology, 107, 1, 48, 53, 08 Feb. 2006, [Peer-reviewed]
English, Scientific journal - IL-6-STAT3 controls intracellular MHC class II alpha beta dimer level through cathepsin S activity in dendritic cells
H Kitamura, H Kamon, SI Sawa, SJ Park, N Katunuma, K Ishihara, M Murakami, T Hirano
IMMUNITY, 23, 5, 491, 502, Nov. 2005, [Peer-reviewed]
English, Scientific journal - IL-6/IL-12関連サイトカインIL-27の機能発現におけるSTAT3の役割
善本 隆之, 大脇 敏之, 浅川 正幸, 森嶋 紀子, 竹田 潔, 村上 正晃, 平野 敏夫, 水口 純一郎
日本免疫学会総会・学術集会記録, 35, 283, 283, (NPO)日本免疫学会, Nov. 2005
Japanese - Coronary pressure measurement to determine treatment strategy for equivocal left main coronary artery lesions
Shunji Suemaru, Kohichiro Iwasaki, Keizo Yamamoto, Shozo Kusachi, Kazuyoshi Hina, Satoshi Hirohata, Minoru Hirota, Masaaki Murakami, Shigeshi Kamikawa, Takashi Murakami, Yasushi Shiratori
Heart and Vessels, 20, 6, 271, 277, Nov. 2005, [Peer-reviewed]
English, Scientific journal - Hyperactivation of gp130-mediated STAT3 signaling induces a rheumatoid arthritis-like disease that is dependent on MHC class II restricted CD4+ T cells
Masaaki Murakami, Shin-ichiro Sawa, Daisuke Kamimura, Hokuto Kamon, Hidemitsu Kitamura, Takaya Kawabe, Park Sung-Joo, Katsuhiko Ishihara, Toshio Hirano
International Congress Series, 1285, 207, 211, Nov. 2005, [Peer-reviewed]
English, Scientific journal - Significant correlation of recruitable coronary collateral blood flow determined by coronary wedge pressure with ST-segment elevation during coronary occlusion
Shigeshi Kamikawa, Kohichiro Iwasaki, Keizo Yamamoto, Shozo Kusachi, Kazuyoshi Hina, Satoshi Hirohata, Masaaki Murakami, Minoru Hirota, Takashi Murakami, Yasushi Shiratori
Coronary Artery Disease, 16, 4, 231, 236, Jun. 2005, [Peer-reviewed]
English, Scientific journal - [Mechanisms for generation and maintenance of memory CD8 T cells].
Kamimura D, Murakami M
Nihon rinsho. Japanese journal of clinical medicine, 63 Suppl 4, 369, 374, Apr. 2005, [Peer-reviewed] - Mechanism of macrophage activation by chitin derivatives
T Mori, M Murakami, M Okumura, T Kadosawa, T Uede, T Fujinaga
JOURNAL OF VETERINARY MEDICAL SCIENCE, 67, 1, 51, 56, Jan. 2005, [Peer-reviewed]
English, Scientific journal - Evidence of a novel IL-2/15R beta-targeted cytokine involved in homeostatic proliferation of memory CD8(+) T cells
D Kamimura, N Ueda, Y Sawa, S Hachida, T Atsumi, T Nakagawa, SI Sawa, GH Jin, H Suzuki, K Ishihara, M Murakami, T Hirano
JOURNAL OF IMMUNOLOGY, 173, 10, 6041, 6049, Nov. 2004, [Peer-reviewed]
English, Scientific journal - IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation
SJ Park, T Nakagawa, H Kitamura, T Atsumi, H Kamon, S Sawa, D Kamimura, N Ueda, Y Iwakura, K Ishihara, M Murakami, T Hirano
JOURNAL OF IMMUNOLOGY, 173, 6, 3844, 3854, Sep. 2004, [Peer-reviewed]
English, Scientific journal - New IL-6 (gp130) family cytokine members, CLC/NNT1/BSF3 and IL-27
M Murakami, D Kamimura, T Hirano
GROWTH FACTORS, 22, 2, 75, 77, Jun. 2004, [Peer-reviewed]
English - The point mutation of tyrosine 759 of the IL-6 family cytokine receptor gp130 synergizes with HTLV-1 pX in promoting rheumatoid arthritis-like arthritis
K Ishihara, S Sawa, H Ikushima, S Hirota, T Atsumi, D Kamimura, SJ Park, M Murakami, Y Kitamura, Y Iwakura, T Hirano
INTERNATIONAL IMMUNOLOGY, 16, 3, 455, 465, Mar. 2004, [Peer-reviewed]
English, Scientific journal - Membrane dynamics and cell signaling as studied by single molecule imaging
T Kobayashi, M Murakami, Y Takeda, A Kusumi, A Yoshimura
SEIKAGAKU, 76, 2, 91, 100, Feb. 2004, [Peer-reviewed]
Japanese - Long-term acceptance of rat cardiac allografts on the basis of adenovirus mediated CD40Ig plus CTLA4Ig gene therapies
K Yamashita, T Masunaga, N Yanagida, M Takehara, T Hashimoto, T Kobayashi, H Echizenya, N Hua, M Fujita, M Murakami, H Furukawa, T Uede, S Todo
TRANSPLANTATION, 76, 7, 1089, 1096, Oct. 2003, [Peer-reviewed]
English, Scientific journal - IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages
H Yasukawa, M Ohishi, H Mori, M Murakami, T Chinen, D Aki, T Hanada, K Takeda, S Akira, M Hoshijima, T Hirano, KR Chien, A Yoshimura
NATURE IMMUNOLOGY, 4, 6, 551, 556, Jun. 2003, [Peer-reviewed]
English, Scientific journal - Critical function of T cell death-associated gene 8 in glucocorticoid-induced thymocyte apoptosis
N Tosa, M Murakami, WY Jia, M Yokoyama, T Masunaga, C Iwabuchi, M Inobe, K Iwabuchi, T Miyazaki, K Onoe, M Iwata, T Uede
INTERNATIONAL IMMUNOLOGY, 15, 6, 741, 749, Jun. 2003, [Peer-reviewed]
English, Scientific journal - Combined gene therapy with adenovirus vectors containing CTLA4Ig and CD40Ig prolongs survival of composite tissue allografts in rat model
K Kanaya, Y Tsuchida, M Inobe, M Murakami, T Hirose, S Kon, S Kawaguchi, T Wada, T Yamashita, S Ishii, T Uede
TRANSPLANTATION, 75, 3, 275, 281, Feb. 2003, [Peer-reviewed]
English, Scientific journal - [Role of cytokines for maintenance of memory CD8+ T cells].
Kamon H, Murakami M
Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme, 47, 2313, 2317, 16 Suppl, Dec. 2002, [Peer-reviewed] - RANTES production by memory phenotype T cells is controlled by a posttranscriptional, TCR-dependent process
BJ Swanson, M Murakami, TC Mitchell, J Kappler, P Marrack
IMMUNITY, 17, 5, 605, 615, Nov. 2002, [Peer-reviewed]
English, Scientific journal - Intrinsic and extrinsic manipulation of B7/CTLA-4 interaction for induction of anti-tumor immunity against osteosarcoma cells
M Nagamori, S Kawaguchi, M Murakami, T Wada, S Nagoya, T Yamashita, M Inobe, T Uede
ANTICANCER RESEARCH, 22, 6A, 3223, 3227, Nov. 2002, [Peer-reviewed]
English, Scientific journal - In vivo immunogenicity of osteosarcoma cells that express B7-1a, an alternatively spliced form of B7-1
M Nagamori, S Kawaguchi, M Murakami, T Wada, M Inobe, S Ishii, T Uede
ANTICANCER RESEARCH, 22, 4, 2009, 2013, Jul. 2002, [Peer-reviewed]
English, Scientific journal - Overexpression of the Wilms' tumor gene WT1 in de novo lung cancers
Y Oji, S Miyoshi, H Maeda, S Hayashi, H Tamaki, SI Nakatsuka, M Yao, E Takahashi, Y Nakano, H Hirabayashi, Y Shintani, Y Oka, A Tsuboi, N Hosen, M Asada, T Fujioka, M Murakami, K Kanato, M Motomura, EH Kim, M Kawakami, K Ikegame, H Ogawa, K Aozasa, Kawase, I, H Sugiyama
INTERNATIONAL JOURNAL OF CANCER, 100, 3, 297, 303, Jul. 2002, [Peer-reviewed]
English, Scientific journal - Combination treatment with FTY720 and CTLA4IgG preserves the respiratory epithelium and prevents obliterative disease in a murine airway model
K Konishi, M Inobe, A Yamada, M Murakami, S Todo, T Uede
JOURNAL OF HEART AND LUNG TRANSPLANTATION, 21, 6, 692, 700, Jun. 2002, [Peer-reviewed]
English, Scientific journal - CD25+CD4+T cells contribute to the control of memory CD8+T cells
M Murakami, A Sakamoto, J Bender, J Kappler, P Marrack
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 99, 13, 8832, 8837, Jun. 2002, [Peer-reviewed]
English, Scientific journal - Induction of donor-specific tolerance by adenovirus-mediated CD40Ig gene therapy in rat liver transplantation
M Nomura, K Yamashita, M Murakami, M Takehara, H Echizenya, M Sunahara, N Kitagawa, M Fujita, H Furukawa, T Uede, S Todo
TRANSPLANTATION, 73, 9, 1403, 1410, May 2002, [Peer-reviewed]
English, Scientific journal - Development of atherosclerosis in osteopontin transgenic mice
S Chiba, H Okamoto, S Kon, C Kimura, M Murakami, M Inobe, Y Matsui, T Sugawara, T Shimizu, T Uede, A Kitabatake
HEART AND VESSELS, 16, 3, 111, 117, Mar. 2002, [Peer-reviewed]
English, Scientific journal - Feasibility of immunosuppression in composite tissue allografts by systemic administration of CTLA4Ig
N Iwasaki, T Gohda, C Yoshioka, A Murakami, M Inobe, A Minami, T Uede
TRANSPLANTATION, 73, 3, 334, 340, Feb. 2002, [Peer-reviewed]
English, Scientific journal - Evaluation effects of chitosan for the extracellular matrix production by fibroblasts and the growth factors production by macrophages
H Ueno, F Nakamura, M Murakami, M Okumura, T Kadosawa, T Fujinaga
BIOMATERIALS, 22, 15, 2125, 2130, Aug. 2001, [Peer-reviewed]
English, Scientific journal - Successful gene therapy via intraarticular injection of adenovirus vector containing CTLA4IgG in a murine model of type II collagen-induced arthritis
K Ijima, M Murakami, H Okamoto, M Inobe, S Chikuma, Saito, I, Y Kanegae, Y Kawaguchi, A Kitabatake, T Uede
HUMAN GENE THERAPY, 12, 9, 1063, 1077, Jun. 2001, [Peer-reviewed]
English, Scientific journal - Chitosan accelerates the production of osteopontin from polymorphonuclear leukocytes
H Ueno, M Murakami, M Okumura, T Kadosawa, T Uede, T Fujinaga
BIOMATERIALS, 22, 12, 1667, 1673, Jun. 2001, [Peer-reviewed]
English, Scientific journal - Long-term acceptance of allografts by in vivo gene transfer of regulatable adenovirus vector containing CTLA4IgG and loxP
M Takehara, M Murakami, M Inobe, K Tanaka, S Chikuma, Saito, I, Y Kanegae, Y Yasunami, M Nakano, K Yamashita, S Todo, T Uede
HUMAN GENE THERAPY, 12, 4, 415, 426, Mar. 2001, [Peer-reviewed]
English, Scientific journal - Novel CD40-IgG adenovirus-mediated gene therapy as a potent immunosuppressive treatment for liver transplantation in rats
M Nomura, K Yamashita, M Murakami, M Takehara, M Konishi, H Echizenya, N Yanagida, M Sunahara, N Kitagawa, H Furukawa, T Uede, S Todo
TRANSPLANTATION PROCEEDINGS, 33, 1-2, 189, 189, Feb. 2001, [Peer-reviewed]
English, Scientific journal - Tolerance induction by a single donor pretreatment with the adenovirus vector encoding CTLA4Ig gene in rat orthotopic liver transplantation
N Yanagida, M Nomura, K Yamashita, M Takehara, M Murakami, H Echizenya, K Konishi, N Kitagawa, H Furukawa, T Uede, S Todo
TRANSPLANTATION PROCEEDINGS, 33, 1-2, 573, 574, Feb. 2001, [Peer-reviewed]
English, Scientific journal - CTLA4IgG gene delivery prevents autoantibody production and lupus nephritis in MRL/lpr mice
M Takiguchi, M Murakami, Nakagawa, I, Saito, I, A Hashimoto, T Uede
LIFE SCIENCES, 66, 11, 991, 1001, Feb. 2000, [Peer-reviewed]
English, Scientific journal - ラット脾臓より抽出した樹状突起細胞のアロ抗原特異的T細胞刺激機序の解析
臼木 智哲, 原田 浩, 竹内 一郎, 小柳 知彦, 猪部 学, 村上 正晃, 上出 利光
日本泌尿器科学会雑誌, 91, 3, 217, 217, 一般社団法人 日本泌尿器科学会, 2000
Japanese - Janus Kinase 2 is associated with a box 1-like motif and phosphorylates a critical tyrosine residue in the cytoplasmic region of cytotoxic T lymphocyte associated molecule-4
Shunsuke Chikuma, Masaaki Murakami, Kumiko Tanaka, Toshimitsu Uede
Journal of Cellular Biochemistry, 78, 2, 241, 250, Wiley-Liss Inc., 2000, [Peer-reviewed]
English, Scientific journal - Abortive alloantigen presentation by donor dendritic cells leads to donor-specific tolerance: a study with a preoperative CTLA4Ig inoculation
H Harada, H Ishikura, Nakagawa, I, J Shindou, M Murakami, T Uede, T Koyanagi, T Yoshiki
UROLOGICAL RESEARCH, 28, 1, 69, 74, Jan. 2000, [Peer-reviewed]
English, Scientific journal - Involvement of CD28/CTLA4-B7 costimulatory pathway in the development of lymphadenopathy and splenomegaly in MRL/lpr mice
M Takiguchi, M Murakami, Nakagawa, I, MM Rashid, N Tosa, S Chikuma, A Hashimoto, T Uede
JOURNAL OF VETERINARY MEDICAL SCIENCE, 62, 1, 29, 36, Jan. 2000, [Peer-reviewed]
English, Scientific journal - The role of osteopontin in the development of granulomatous lesions in lung.
S Chiba, M M Rashid, H Okamoto, H Shiraiwa, S Kon, M Maeda, M Murakami, M Inobe, A Kitabatake, A F Chambers, T Uede
Microbiology and immunology, 44, 4, 319, 32, 2000, [Peer-reviewed], [International Magazine]
English, Osteopontin (OPN) has been shown to be expressed by cells in granulomas of various origins, but whether it plays a functional role in granuloma formation is not known. Here we used a cardiomyopathic hamster (TO2) model, to test the hypothesis that OPN contributes functionally to granuloma development. We immunized cardiomyopathic and normal hamsters by subcutaneous injection of bovine serum albumin in complete Freund's adjuvant, and assessed various tissues for both OPN RNA expression and granuloma formation. Cardiomyopathic hamsters expressed OPN, and formed granulomatous lesions, in heart tissue in both immunized and untreated animals. In addition, immunization induced expression of OPN in lung and lymph nodes of cardiomyopathic (but not normal) hamsters, and also induced granuloma formation in these organs. To test whether OPN expression could play a functional role in inducing granulomas, we produced an adenoviral vector containing the murine OPN gene, and introduced this vector intratracheally into the lungs of normal hamsters. The OPN-containing vector, but not the control vector, induced pulmonary granuloma formation. These studies provided direct in vivo evidence that OPN can contribute functionally to the formation of granulomatous lesions, and suggest that OPN expression may be a common factor involved in formation of granulomas of various origin. - アデノウイルスベクターを用いた CTLA 4 Ig 遺伝子導入による移植後免疫反応の制御
上出 利光, 村上 正晃, 竹原 めぐみ, 藤堂 省
日本臨床免疫学会会誌 = Japanese journal of clinical immunology, 22, 6, 417, 417, 日本臨床免疫学会, 31 Dec. 1999
Japanese - Topical CTLA4-lg suppresses ongoing mucosal immune response in presensitized murine model of allergic rhinitis
J Sato, K Asakura, M Murakami, T Uede, A Kataura
INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY, 119, 3, 197, 204, Jul. 1999, [Peer-reviewed]
English, Scientific journal - Blockade of CD28/CTLA4-B7 pathway prevented autoantibody-related diseases but not lung disease in MRL/lpr mice
M Takiguchi, M Murakami, Nakagawa, I, A Yamada, S Chikuma, Y Kawaguchi, A Hashimoto, T Uede
LABORATORY INVESTIGATION, 79, 3, 317, 326, Mar. 1999, [Peer-reviewed]
English, Scientific journal - CTLA4IgG treatment induces long-term acceptance of rat small bowel allografts
K Tarumi, M Murakami, A Yagihashi, Nakagawa, I, K Hirata, T Uede
TRANSPLANTATION, 67, 4, 520, 525, Feb. 1999, [Peer-reviewed]
English, Scientific journal - Suppressive effects of CTLA4-IG on nasal allergic reactions in presensitized murine model
J Sato, K Asakura, M Murakami, T Uede, A Kataura
LIFE SCIENCES, 64, 9, 785, 795, Jan. 1999, [Peer-reviewed]
English, Scientific journal - CD44 variants but not CD44s cooperate with beta 1-containing integrins to permit cells to bind to osteopontin independently of arginine-glycine-aspartic acid, thereby stimulating cell motility and chemotaxis
YU Katagiri, J Sleeman, H Fujii, P Herrlich, H Hotta, K Tanaka, S Chikuma, H Yagita, K Okumura, M Murakami, Saiki, I, AF Chambers, T Uede
CANCER RESEARCH, 59, 1, 219, 226, Jan. 1999
English, Scientific journal - Introduction of an osteopontin gene confers the increase in B1 cell population and the production of anti-DNA autoantibodies
Junko Iizuka, Yohko Katagiri, Norihiro Tada, Masaaki Murakami, Tohru Ikeda, Masahiro Sato, Katsuiku Hirokawa, Seiji Okada, Masahiko Hatano, Takeshi Tokuhisa, Toshimitsu Uede
Laboratory Investigation, 78, 12, 1523, 1533, Dec. 1998, [Peer-reviewed]
English, Scientific journal - The mechanism by which proteolysis enhances the ligand-binding activity of guinea pig type II Fc receptor for IgG (Fc gamma RIIB)
Y Isashi, T Yamashita, S Nagasawa, K Tanaka, M Murakami, T Uede
JOURNAL OF BIOCHEMISTRY, 123, 5, 959, 967, May 1998, [Peer-reviewed]
English, Scientific journal - Expression and co-stimulatory function of B7-2 on murine CD4+ T cells
Rie Hakamada-Taguchi, Takuma Kato, Hiroshi Ushijima, Masaaki Murakami, Toshimitsu Uede, Hideo Nariuchi
European Journal of Immunology, 28, 3, 865, 873, Mar. 1998, [Peer-reviewed]
English, Scientific journal - Vaccination with B7-1(+) tumor and anti-adhesion therapy with RGD pseudo-peptide (FC-336) efficiently induce anti-metastatic effect
H Fujii, M Inobe, Y Hayakawa, F Kimura, M Murakami, Y Onishi, Azuma, I, T Uede, Saiki, I
CLINICAL & EXPERIMENTAL METASTASIS, 16, 2, 141, 148, Mar. 1998, [Peer-reviewed]
English, Scientific journal - Prolongation of rat small bowel allograft survival of CTLA-4 IG
K. Tarumi, A. Yagihashi, M. Murakami, T. Uede, K. Hirata
Transplantation Proceedings, 30, 6, 2596, 2599, 1998, [Peer-reviewed]
English, International conference proceedings - The functional role of B7 molecules on the induction of thymocyte activation and apoptosis
N Aoki, M Inobe, M Murakami, R Abe, H Iizuka
MICROBIOLOGY AND IMMUNOLOGY, 42, 8, 555, 565, 1998, [Peer-reviewed]
English, Scientific journal - B7-1-transfected tumor vaccine counteracts chemotherapy-induced immunosuppression and prolongs the survival of rats bearing highly metastatic osteosarcoma cells
M Hayakawa, S Kawaguchi, S Ishii, M Murakami, T Uede
INTERNATIONAL JOURNAL OF CANCER, 71, 6, 1091, 1102, Jun. 1997, [Peer-reviewed]
English, Scientific journal - Vascularized bone marrow allotransplantation in rats prolongs a simultaneous skin allograft
Y Tsuchida, M Usui, M Murakami, T Uede
TRANSPLANTATION PROCEEDINGS, 29, 3, 1732, 1733, May 1997, [Peer-reviewed]
English, Scientific journal - Involvement of a common 10-amino-acid segment in the cytoplasmic region of CD40 but different MAP kinases in different CD40-mediated responses
Toyomichi Hara, Masaaki Murakami, Hiroaki Maeda, Masahiko Hibi, Toshimitsu Uede
Biochemical and Biophysical Research Communications, 233, 1, 187, 192, Academic Press Inc., 07 Apr. 1997, [Peer-reviewed]
English, Scientific journal - Limb allografts in rats treated with anti-ICAM-1 and anti-LFA-1 monoclonal antibodies
Yoshihiko Tsuchida, Masamichi Usui, Takafumi Naitoh, Terukazu Takahashi, Masaaki Murakami, Toshimitsu Uede
Journal of Reconstructive Microsurgery, 13, 2, 107, 110, Thieme Medical Publishers, Inc., 1997, [Peer-reviewed]
English, Scientific journal - Molecular cloning and characterization of guinea pig Fc gamma RIII: Expression but not function is independent of the gamma chain of Fc epsilon RI
Y Isashi, T Yamashita, S Nagasawa, M Murakami, T Uede
INTERNATIONAL IMMUNOLOGY, 8, 9, 1335, 1346, Sep. 1996, [Peer-reviewed]
English, Scientific journal - Non-RGD domains of osteopontin promote cell adhesion without involving αv integrins
Yohko U. Katagiri, Masaaki Murakami, Kiyoshi Mori, Junko Iizuka, Toyomichi Hara, Kumiko Tanaka, Wen-Yi Jia, Ann F. Chambers, Toshimitsu Uede
Journal of Cellular Biochemistry, 62, 1, 123, 131, Jul. 1996, [Peer-reviewed]
English, Scientific journal - The role of the B7-1a molecule, an alternatively spliced form of murine B7-1 (CD80), on T cell activation
M Inobe, N Aoki, PS Linsley, JA Ledbetter, R Abe, M Murakami, T Uede
JOURNAL OF IMMUNOLOGY, 157, 2, 582, 588, Jul. 1996, [Peer-reviewed]
English, Scientific journal - Identification and characterization of an alternative cytotoxic T lymphocyte-associated protein 4 binding molecule on B cells
M Murakami, Y Takahashi, Y Isashi, S Kon, WY Jia, M Inobe, R Abe, T Uede
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 93, 15, 7838, 7842, Jul. 1996, [Peer-reviewed]
English, Scientific journal - Vaccination of tumor cells transfected with the B7-1 (CD80) gene induces the anti-metastatic effect and tumor immunity in mice
H Fujii, M Inobe, F Kimura, J Murata, M Murakami, Y Onishi, Azuma, I, T Uede, Saiki, I
INTERNATIONAL JOURNAL OF CANCER, 66, 2, 219, 224, Apr. 1996, [Peer-reviewed]
English, Scientific journal - CD28 co-stimulatory signals induce IL-2 receptor expression on antigen-stimulated virgin T cells by an IL-2-independent mechanism
K Toyooka, S Maruo, T Iwahori, N Yamamoto, XG Tai, R Abe, Y Takahama, M Murakami, T Uede, T Hamaoka, H Fujiwara
INTERNATIONAL IMMUNOLOGY, 8, 2, 159, 169, Feb. 1996, [Peer-reviewed]
English, Scientific journal - Long-term acceptance of major histocompatibility complex-mismatched cardiac allograft induced by a low dose of CTLA4IgM plus FK506
A Yamada, M Murakami, K Ijima, H Yagita, K Okumura, S Komatsu, T Uede
MICROBIOLOGY AND IMMUNOLOGY, 40, 7, 513, 518, 1996
English, Scientific journal - Functional Analysis of the Osteopontin Molecule
YOHKO KATAGIRI, KIYOSHI MORI, TOYOMICHI HARA, KUMIKO TANAKA, MASAAKI MURAKAMI, TOSHIMITSU UEDE
Annals of the New York Academy of Sciences, 760, 1, 371, 374, 1995, [Peer-reviewed]
English, Scientific journal - The rat neutrophil low-affinity Fc receptor for IgG: molecular cloning and functional characterization
Yasuhiro Isashi, Masatada Tamakoshi, Yumiko Nagai, Tetsuo Sudo, Masaaki Murakami, Toshimitsu Uede
Immunology Letters, 46, 1-2, 157, 163, 1995, [Peer-reviewed]
English, Scientific journal - Neutrophil-independent myocardial dysfunction during an early stage of global ischemia and reperfusion of isolated hearts
Yasuhiro Kamikubo, Masaaki Murakami, Michiaki Imamura, Toshifumi Murashita, Keishu Yasuda, Toshimitsu Uede
Immunopharmacology, 29, 3, 261, 271, 1995, [Peer-reviewed]
English, Scientific journal - IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase
Masaaki Murakami, Masahiko Hibi, Naoko Nakagawa, Toshimasa Nakagawa, Kiyoshi Yasukawa, Koichi Yamanishi, Tetsuya Taga, Tadamitsu Kishimoto
Science, 260, 5115, 1808, 1810, 1993, [Peer-reviewed]
English, Scientific journal - INTERLEUKIN-6 RECEPTOR AND SIGNALS
T TAGA, M HIBI, M MURAKAMI, M SAITO, H YAWATA, M NARAZAKI, Y HIRATA, T SUGITA, K YASUKAWA, T HIRANO, T KISHIMOTO
CHEMICAL IMMUNOLOGY, 51, 181, 204, 1992, [Peer-reviewed]
English - Regulation of IL-6 receptor and GP130 expression on human cell lines of lymphoid and myeloid origin
Andras Falus, Tetsuya Taga, Masahiko Hibi, Masaaki Murakami, Tadamitsu Kishimoto
Cytokine, 4, 6, 495, 499, 1992, [Peer-reviewed]
English, Scientific journal - Critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the cytokine receptor family
Masaaki Murakami, Masashi Narazaki, Masahiko Hibi, Hideo Yawata, Kiyoshi Yasukawa, Michinari Hamaguchi, Tetsuya Taga, Tadamitsu Kishimoto
Proceedings of the National Academy of Sciences of the United States of America, 88, 24, 11349, 11353, National Academy of Sciences, 1991, [Peer-reviewed]
English, Scientific journal - MOLECULAR-CLONING AND EXPRESSION OF AN IL-6 SIGNAL TRANSDUCER, GP130
M HIBI, M MURAKAMI, M SAITO, T HIRANO, T TAGA, T KISHIMOTO
CELL, 63, 6, 1149, 1157, Dec. 1990, [Peer-reviewed]
English, Scientific journal - INTERLEUKIN-6 (IL-6) AND ITS RECEPTOR (IL-6R) IN MYELOMA PLASMACYTOMA
S SUEMATSU, M HIBI, T SUGITA, M SAITO, M MURAKAMI, T MATSUSAKA, T MATSUDA, T HIRANO, T TAGA, T KISHIMOTO
CURRENT TOPICS IN MICROBIOLOGY AND IMMUNOLOGY, 166, 13, 22, 1990, [Peer-reviewed]
English, Scientific journal - Interleukin 6 and its receptor in the immune response and hematopoiesis
Toshio Hirano, Tetsuya Taga, Tadashi Matsuda, Masahiko Hibi, Sachiko Suematsu, Bo Tang, Masaaki Murakami, Tadamitsu Kishimoto
The International Journal of Cell Cloning, 8, 1 S, 155, 167, 1990, [Peer-reviewed]
English, Scientific journal - IL-6 AND IL-6 RECEPTOR
M MURAKAMI, T HIRANO
SEIKAGAKU, 62, 1, 32, 35, Jan. 1990, [Peer-reviewed]
Japanese, Scientific journal - Massive subcutaneous hemangiosarcoma in a dog.
藤永徹, 諏訪隆彦, 成清美智代, 奥村正裕, 井上久美子, 滝口満喜, 村上正晃, 田島誉士, 大友勘十郎
日本獣医師会雑誌, 42, 7, 491, 494, 1989, [Peer-reviewed]
Other Activities and Achievements
- Discovery of the remote inflammation gateway reflection
石井明日香, 長谷部理絵, 村上正晃, 医学のあゆみ, 285, 7, 2023 - 遠隔炎症ゲートウェイ反射:ATP-感覚神経-介在神経のクロストークによる遠隔部位での左右対称性炎症の誘導機構
長谷部理絵, 村上薫, 田中勇希, 村上正晃, 村上正晃, 村上正晃, 日本解剖学会総会・全国学術集会抄録集(CD-ROM), 128th, 2023 - Chronic calcineurin inhibitors nephrotoxicity is an inflammation state, which can be suppressed by steroid treatment
岩原直也, 堀田記世彦, 田中勇希, 高橋郁子, 長谷部理絵, 岡田宏美, 辻隆裕, 高田祐輔, 樋口はるか, 佐々木元, 田邉起, 篠原信雄, 村上正晃, 日本泌尿器科学会総会(Web), 110th, 2023 - A mechanism of tissue specific inflammation induced by the gateway reflex
長谷部理絵, 村上薫, 山崎剛士, 田中宏樹, 村上正晃, 村上正晃, 村上正晃, 実験医学, 41, 20, 2023 - 【BBB-単なる障壁ではない】正常におけるメカニズム BBBにおける免疫細胞の侵入口形成機構,ゲートウェイ反射について
西 李依子, 村上 薫, 長谷部 理絵, 村上 正晃, Clinical Neuroscience, 40, 12, 1544, 1548, Dec. 2022
(株)中外医学社, Japanese - 透明化した脳組織を用いたウエストナイルウイルスの中枢神経組織侵入機構の解析
福田幸音, 高橋侑嗣, 佐々木道仁, 長谷部理絵, 村上正晃, 村上正晃, 村上正晃, 苅和宏明, 小林進太郎, 日本ウイルス学会学術集会プログラム・予稿集(Web), 69th, 2022 - サイトカインストームとIL-6アンプ—特集 コロナウイルス感染の免疫学
村上 薫, 北條 慎太郎, 田中 くみ子, 村上 正晃, 炎症と免疫 / 「炎症と免疫」編集委員会 編, 30, 1, 18, 27, Jan. 2022
Japanese - Gateway Reflex and Mechanotransduction
Shiina Matsuyama, Yuki Tanaka, Rie Hasebe, Shintaro Hojyo, Masaaki Murakami, Frontiers in Immunology, 12, 22 Dec. 2021
Book review - ループスモデルマウスにおける慢性ストレス誘導性IL-12/23p40による精神神経病態への影響
阿部 靖矢, 藤枝 雄一郎, 奥 健志, 河野 通仁, 田中 勇希, 加藤 将, 有沼 良幸, 佐藤 和貴郎, 村上 正晃, 渥美 達也, 日本臨床免疫学会総会プログラム・抄録集, 49回, 73, 73, Oct. 2021
(一社)日本臨床免疫学会, Japanese - Identification of pathogenic Single Nucleotide Polymorphism in Inflammatory Colorectal Polyps of Miniature Dachshunds(和訳中)
Bin Teoh Yong, 永田 矩之, 大田 寛, 佐々木 東, 中村 健介, 村上 正晃, 滝口 満喜, 日本獣医学会学術集会講演要旨集, 164回, [HSO, 32], Sep. 2021
(公社)日本獣医学会, English - Regulation of autoimmune disease by the Gateway Reflex, a potential therapeutic target for neuromodulation
長谷部理絵, 村上正晃, 医学のあゆみ, 277, 9, 2021 - ATPによる感覚神経-介在神経回路の活性化は遠隔部位での炎症反応を誘導する
長谷部理絵, 田中勇希, 北條慎太郎, 村上正晃, 日本インターフェロン・サイトカイン学会学術集会抄録集, 85th (CD-ROM), 2021 - ショック管理 2021-’22-ガイドライン,スタンダード,論点そして私見-VII.ショックと新たな知見/治療法 新たな神経系と免疫系の相互作用:ゲートウェイ反射と炎症反射
久保田晋平, 久保田晋平, 長谷部理絵, 村上正晃, 村上正晃, 救急・集中治療, 33, 3, 2021 - Orosomucoid 1 is involved in the development of chronic allograft rejection after kidney transplantation.
Haruka Higuchi, Daisuke Kamimura, Jing-Jing Jiang, Toru Atsumi, Daiki Iwami, Kiyohiko Hotta, Hiroshi Harada, Yusuke Takada, Hiromi Kanno-Okada, Kanako C Hatanaka, Yuki Tanaka, Nobuo Shinohara, Masaaki Murakami, International immunology, 32, 5, 335, 346, 08 May 2020, [International Magazine]
Chronic allograft rejection is the most common cause of long-term allograft failure. One reason is that current diagnostics and therapeutics for chronic allograft rejection are very limited. We here show that enhanced NFκB signaling in kidney grafts contributes to chronic active antibody-mediated rejection (CAAMR), which is a major pathology of chronic kidney allograft rejections. Moreover, we found that urinary orosomucoid 1 (ORM1) is a candidate marker molecule and therapeutic target for CAAMR. Indeed, urinary ORM1 concentration was significantly higher in kidney transplant recipients pathologically diagnosed with CAAMR than in kidney transplant recipients with normal histology, calcineurin inhibitor toxicity, or interstitial fibrosis and tubular atrophy. Additionally, we found that kidney biopsy samples with CAAMR expressed more ORM1 and had higher NFκB and STAT3 activation in tubular cells than samples from non-CAAMR samples. Consistently, ORM1 production was induced after cytokine-mediated NFκB and STAT3 activation in primary kidney tubular cells. The loss- and gain-of-function of ORM1 suppressed and promoted NFκB activation, respectively. Finally, ORM1-enhanced NFκB-mediated inflammation development in vivo. These results suggest that an enhanced NFκB-dependent pathway following NFκB and STAT3 activation in the grafts is involved in the development of chronic allograft rejection after kidney transplantation and that ORM1 is a non-invasive candidate biomarker and possible therapeutic target for chronic kidney allograft rejection., English - マウスモデルにおける抗リン脂質抗体の精神神経症状や中枢神経系細胞への影響
阿部靖矢, 阿部靖矢, 奥健志, 狩野皓平, 河野通仁, 藤枝雄一郎, AMENGUAL Olga, 田中勇希, 上村大輔, 保田晋助, 村上正晃, 渥美達也, 日本臨床免疫学会総会プログラム・抄録集, 47th, 74, 74, 2019
(一社)日本臨床免疫学会, Japanese - デング熱重症化マウスモデルでは,ガンマ・デルタT細胞から産生されたIL-17AがIL-6産生を増強し,血漿漏出を伴う致死的感染を引き起こしている
黒須剛, 奥崎大介, PHANTHANAWIBOON Supranee, 吉河智城, 下島昌幸, 村上正晃, 上村大輔, 永田典代, 岩田奈織子, 西条政幸, 日本分子生物学会年会プログラム・要旨集(Web), 42nd, 2019 - 膵癌ドライバー変異はARF6-AMAP1経路を活性化し悪性度と免疫回避能を促進する(Pancreatic KRAS and TP53 oncogenes cooperatively activate ARF6-AMAP1 pathway to drive malignancy and immune evasion)
橋本 あり, 橋本 茂, 古川 聖太郎, 蔦保 暁生, 小野寺 康仁, 大塚 勇太郎, 半田 悠, 及川 司, 水上 裕輔, 村上 正晃, 平野 聡, 佐邊 壽孝, 日本癌学会総会記事, 77回, 2219, 2219, Sep. 2018
日本癌学会, English - 軟骨細胞にはNF-κB Arthritis Inducer 1を介する炎症回路活性化機構が存在する
太田 光俊, 田中 勇希, 有馬 康伸, 上村 大輔, 小野寺 智洋, 村上 正晃, 岩崎 倫政, 北海道整形災害外科学会雑誌, 60, 1, 164, 164, Aug. 2018
北海道整形災害外科学会, Japanese - Photopic light intensity inhibits retinal inflammation via down-regulating local adrenergic system
Daisuke Kamimura, Andrea Stofkova, Takuto Ohki, Yasunobu Arima, Masaaki Murakami, CYTOKINE, 100, 51, 52, Dec. 2017
English, Summary international conference - Brain micro-inflammation at specific vessels establishes a new neural circuit, which dysregulates the gastrointestinal homeostasis under stress conditions
Yasunobu Arima, Takuto Ohki, Naoki Nishikawa, Kotaro Higuchi, Junko Nio-Kobayashi, Stofkova Andrea, Toshihiko Iwanaga, Marco Prinz, Daisuke Kamimura, Masaaki Murakami, CYTOKINE, 100, 52, 52, Dec. 2017
English, Summary international conference - Stress-gateway reflex: Chronic stress induces fatal organ dysfunctions through a new neural circuit
Masaaki Murakami, Clinical and Experimental Neuroimmunology, 8, 4, 283, 284, 01 Nov. 2017
Wiley-Blackwell, English, Report scientific journal - Existence of IL-6 and IL-17 Mediated Inflammation Amplifier Loop in Reactive Arthritis
Ramnath Misra, Sandeep Kumar, Rajeev Singh, Abhisek Singh, Daisuke Kamimura, Smriti Chaurasia, Yasunobu Aria, Tori Austria, Ratnadeep Mukherjee, Balachandran Ravindran, Vikas Agarwal, Masaaki Murakami, ARTHRITIS & RHEUMATOLOGY, 69, Oct. 2017
English, Summary international conference - Targeting molecules involved in immune cell trafficking to the central nervous system for therapy in multiple sclerosis
Mohamed Elfeky, Daisuke Kamimura, Yasunobu Arima, Masaaki Murakami, Lawrence Steinman, Clinical and Experimental Neuroimmunology, 8, 3, 183, 191, 01 Aug. 2017
Wiley-Blackwell, English, Book review - 軟骨細胞にはNF-κB arthritis inducer 1を介する炎症回路活性化機構が存在する
太田 光俊, 田中 勇希, 蒋 菁菁, 中川 育磨, 樋口 はるか, 藤田 宗純, 有馬 康伸, 熱海 徹, 上村 大輔, 小野寺 智洋, 村上 正晃, 岩崎 倫政, 日本整形外科学会雑誌, 91, 8, S1728, S1728, Aug. 2017
(公社)日本整形外科学会, Japanese - Regulation of immune cell gateways in organs and a dementia including Alzheimer's diseases
有馬 康伸, 上村 大輔, 村上 正晃, Dementia Japan : 日本認知症学会誌, 31, 2, 265, 273, May 2017
日本認知症学会, Japanese - Activation of Inflammation Amplifier in Kidney Graft and Urinary Biomarker for Chronic Rejection
H. Higuchi, D. Iwami, K. Hotta, N. Shinohara, M. Murakami, AMERICAN JOURNAL OF TRANSPLANTATION, 17, 720, 720, Apr. 2017
English, Summary international conference - THE ACTIVATION OF INFLAMMATION AMPLIFIER IN KIDNEY TRANSPLANT GRAFT AND URINARY BIOMARKER FOR CHRONIC REJECTION
Haruka Higuchi, Daiki Iwami, Kiyohiko Hotta, Nobuo Shinohara, Masaaki Murakami, JOURNAL OF UROLOGY, 197, 4, E76, E76, Apr. 2017
English, Summary international conference - Gateway reflexes: A new paradigm of neuroimmune interactions
Takuto Ohki, Daisuke Kamimura, Yasunobu Arima, Masaaki Murakami, Clinical and Experimental Neuroimmunology, 8, 1, 23, 32, 01 Feb. 2017
Wiley-Blackwell, English, Book review - Computer model analysis of the difference between F759 and wild type mice in rheumatoid-like arthritis emergence
S. Yamada, A. Yoshimura, T. Atsumi, M. Murakami, EUROPEAN JOURNAL OF IMMUNOLOGY, 46, 53, 53, Aug. 2016
English, Summary international conference - A novel regulator of NF kappa B signaling enhances I kappa B alpha ubiquitination and promotes inflammatory disease development
Y. Okuyama, T. Atsumi, J. -J Jiang, A. Nakamura, H. Ogura, J. Meng, D. Kamimura, N. Shii, T. Hirano, M. Murakami, EUROPEAN JOURNAL OF IMMUNOLOGY, 46, 410, 410, Aug. 2016
English, Summary international conference - Inflammation Amplifier, a Chemokine Inducer in Non-Immune Cells in Kidney Transplantation Graft.
H. Higuchi, H. Bando, J. Jing-Jing, T. Atsumi, D. Iwami, K. Morita, N. Shinohara, M. Murakami, AMERICAN JOURNAL OF TRANSPLANTATION, 16, 605, 605, Jun. 2016
English, Summary international conference - Regulation of Immune Cell Gateways in Organs
上村 大輔, 有馬 康伸, 村上 正晃, 最新医学, 71, 2, 176, 187, Feb. 2016
最新医学社, Japanese - Pain is an inducer for relapse in multiple sclerosis models through a regional neural signal
Yasunobu Arima, Kotaro Higuchi, Naoki Nishikawa, Andrea Stofkova, Takuto Ohki, Daisuke Kamimura, Masaaki Murakami, Clinical and Experimental Neuroimmunology, 6, 4, 343, 344, 01 Nov. 2015
Wiley-Blackwell, English, Report scientific journal - Immune cell gateways in the central nervous system regulated by regional neural stimulations
Daisuke Kamimura, Andrea Stofkova, Naoki Nishikawa, Toru Atsumi, Yasunobu Arima, Masaaki Murakami, Clinical and Experimental Neuroimmunology, 6, 2, 120, 128, 01 May 2015
Wiley-Blackwell, English, Book review - In Vivo Expansion of Donor-Specific Regulatory T Cells by a New Triazolopyrimidine Derivative and Donor-Specific Transfusion
S. Emoto, R. Goto, S. Shibasaki, A. Nagatsu, H. Ono, R. Igarashi, M. Fukai, T. Shimamura, K. Saiga, M. Murakami, A. Taketomi, S. Todo, K. Yamashita, AMERICAN JOURNAL OF TRANSPLANTATION, 15, May 2015
English, Summary international conference - In vivo MRI monitoring of inflammatory alterations and cellular dynamics in the central nervous system
Yuki Mori, Yasunobu Arima, Ting Chen, Dasong Zhu, Yutaka Komai, Masaaki Murakami, Yoshichika Yoshioka, Tetsuya Fujisawa, Syoji Kobashi, Yutaka Hata, World Automation Congress Proceedings, 355, 360, 24 Oct. 2014, [Peer-reviewed]
English - Inflammation amplifier (IL-6 amplifier) and its targets and regulators
小椋 英樹, 村上 正晃, 臨床免疫・アレルギー科, 59, 3, 265, 273, Mar. 2013
科学評論社, Japanese - IL-6アンプと神経-免疫クロストーク (特集 最新の免疫学 : 自然免疫・獲得免疫)
有馬 康伸, 村上 正晃, 医薬ジャーナル, 49, 2, 109, 116,11, Feb. 2013
医薬ジャーナル社, Japanese - Autoimmune disorder phenotypes in HVCN1 gene deficient mice
Mari Sasaki, Akihiro Tojo, Yoshifumi Okochi, Nana Miyawaki, Daisuke Kamimura, Akihito Yamaguchi, Masaaki Murakami, Yasushi Okamura, JOURNAL OF PHYSIOLOGICAL SCIENCES, 63, S192, S192, 2013
English, Summary international conference - The gateway theory: bridging neural and immune interactions in the CNS
Daisuke Kamimura, Moe Yamada, Masaya Harada, Lavannya Sabharwal, Jie Meng, Hidenori Bando, Hideki Ogura, Toru Atsumi, Yasunobu Arima, Masaaki Murakami, FRONTIERS IN NEUROSCIENCE, 7, 2013
English, Book review - IL-6 amplifier, NF-kappa B-triggered positive feedback for IL-6 signaling, in grafts is involved in allogeneic rejection responses (vol 189, pg 1928, 2012)
J. Lee, T. Nakagiri, T. Oto, M. Harada, E. Morii, Y. Shintani, M. Inoue, Y. Iwakura, S. Miyoshi, M. Okumura, T. Hirano, M. Murakami, JOURNAL OF IMMUNOLOGY, 189, 12, 5997, 5997, Dec. 2012
English, Others - Local microbleeding facilitates IL-6- and IL-17-dependent arthritis in the absence of tissue antigen recognition by activated T cells (vol 208, pg 103, 2011)
Masaaki Murakami, Yuko Okuyama, Hideki Ogura, Shogo Asano, Yasunobu Arima, Mineko Tsuruoka, Masaya Harada, Minoru Kanamoto, Yukihisa Sawa, Yoichiro Iwakura, Kiyoshi Takatsu, Daisuke Kamimura, Toshio Hirano, JOURNAL OF EXPERIMENTAL MEDICINE, 209, 12, 2321, 2321, Nov. 2012
English, Others - Signal regulatory protein alpha (SIRP α)/CD172a regulates eosinophil homeostasis
VERJAN GARCIA Noel, UMEMOTO Eiji, SAITO Yasuyuki, HATA Erina, MATOZAKI Takashi, MURAKAMI Masaaki, JANG Myoung Ho, MIYASAKA Masayuki, 日本免疫学会総会・学術集会記録, 40, 122, 07 Nov. 2011
English - Local microbleeding facilitates IL-6- and IL-17-dependent arthritis in the absence of tissue antigen recognition by activated T cells
Masaaki Murakami, Yuko Okuyama, Hideki Ogura, Shogo Asano, Yasunobu Arima, Mineko Tsuruoka, Masaya Harada, Minoru Kanamoto, Yukihisa Sawa, Yoichiro Iwakura, Kiyoshi Takatsu, Daisuke Kamimura, Toshio Hirano, JOURNAL OF EXPERIMENTAL MEDICINE, 208, 1, 103, 114, Jan. 2011
English - ErratumCombination treatment with IL-2 and anti-IL-2 mAbs reduces tumor metastasis via NK cell activation (vol 20, pg 783, 2008)
Gui-Hua Jin, Toshio Hirano, Masaaki Murakami, INTERNATIONAL IMMUNOLOGY, 22, 5, 411, 411, May 2010
English, Others - Zinc suppresses T(h)17 development via inhibition of STAT3 activation
Chika Kitabayashi, Toshiyuki Fukada, Minoru Kanamoto, Wakana Ohashi, Shintaro Hojyo, Toru Atsumi, Naoko Ueda, Ichiro Azuma, Hiroshi Hirota, Masaaki Murakami, Toshio Hirano, INTERNATIONAL IMMUNOLOGY, 22, 5, 375, 386, May 2010
English - IL-6 positively regulates Foxp3(+)CD8(+) T cells in vivo
Takayuki Nakagawa, Mineko Tsuruoka, Hideki Ogura, Yuko Okuyama, Yasunobu Arima, Toshio Hirano, Masaaki Murakami, INTERNATIONAL IMMUNOLOGY, 22, 2, 129, 139, Feb. 2010
English - 自己免疫性関節炎発しようにおけるTh17細胞の役割
Medical Science Digest, 36(29): 7-10, 2010 - 亜鉛と亜鉛トランスポーター：サイトカイン／増殖因子の情報伝達と病態形成への関与
2010 - Interleukin 6 in autoimmune and inflammatory diseases.
Physical and Biological Sciences, 86(7); 717-730, 2010 - Zinc is an intracellular signaling molecule: early and late signal
2010 - Zinc and Th17-mediated autoimmune diseases
2010 - Regulation of T cell Activation via a Metal Transporter
2010 - Zinc and its transporters: Their roles in intracellular signaling and diseases
2010 - IL-6 plays roles not only for developing Th17 but also for inducing an IL-6 amplifier in autoimmue diseases.
2010 - Hepatic IL-7, which is Induced by TLR–Type I IFN Signaling, Promotes T cell Responses.
2010 - Interleukin 6 in autoimmune and inflammatory diseases.
Physical and Biological Sciences, 86(7); 717-730, 2010 - Combination of IL-2 plus anti-IL-2 mAbs reduces cancer metastasis through activation of NK cells.
2010 - Zinc is an intracellular signaling molecule: early and late signal
2010 - Regulation of T cell Activation via a Metal Transporter
2010 - Immune response controlled by hepatic IL-7
村上 正晃, 澤 幸久, Clinical immunology & allergology, 53, 1, 79, 87, 2010
科学評論社, Japanese - Homeostatic proliferation of CD4+ T cells is involved in the pathogenesis of a mouse model of Omenn syndrome.
2010 - Specific antigen recognition by CD4+ T cells is not required for a MHC class II-associated autoimmune arthritis.
2010 - Zinc and CD4+ T cell-mediated autoimmune diseases
2010 - A zinc finger motif containing protein regulates the activation of the IL-6 amplifier, which is a critical for the development of an autoimmune arthritis.
2010 - Homeostatic proliferation of CD4+ T cells is involved in the pathogenesis of a mouse model of Omenn syndrome.
2010 - IFN-γ from CD8+ T cells, which is regulated by IL-6 signal, is involved in superantigen-mediated CD4+ T cell death.
2010 - Specific antigen recognition by CD4+ T cells is not required for a MHC class II-associated autoimmune arthritis.
2010 - Zinc and CD4+ T cell-mediated autoimmune diseases
2010 - A zinc finger motif containing protein regulates the activation of the IL-6 amplifier, which is a critical for the development of an autoimmune arthritis.
2010 - Zinc-mediated STAT3 suppression is involved in inhibition of autoimmune disease development via regulating Th17 differentiation.
2010 - Zinc and Th17-mediated autoimmune diseases
2010 - 免疫学 肝のIL-7による免疫系制御
医学のあゆみ, 232(2): 149-150, 2010 - 医学のあゆみ【第5土曜特集】「サイトカインと疾患-あらたな病態モデルから治療へ」
医歯薬出版(株), 2010 - IFN-γ from CD8+ T cells, which is regulated by IL-6 signal, is involved in superantigen-mediated CD4+ T cell death.
2010 - Hepatic IL-7, which is Induced by TLR–Type I IFN Signaling, Promotes T cell Responses.
2010 - Zinc-mediated STAT3 suppression is involved in inhibition of autoimmune disease development via regulating Th17 differentiation.
2010 - Combination of IL-2 plus anti-IL-2 mAbs reduces cancer metastasis through activation of NK cells.
2010 - IL-6 plays roles not only for developing Th17 but also for inducing an IL-6 amplifier in autoimmue diseases.
2010 - Hepatic Interleukin-7 Expression Regulates T Cell Responses
Yukihisa Sawa, Yasunobu Arima, Hideki Ogura, Chika Kitabayashi, Jing-Jing Jiang, Toru Fukushima, Daisuke Kamimura, Toshio Hirano, Masaaki Murakami, IMMUNITY, 30, 3, 447, 457, Mar. 2009
English - The recognition of specific antigens is not always required for the development of tissue-specific autoimmune diseases associated with MHC II.
2009 - Impaired STAT activations in an ENU mutant mouse carrying excess memory T cells
2009 - Hepatic IL-7 Regulates CD4+T Cell-mediated Autoimmune diseases.
2009 - IFN-gamma expression in CD8(+) T cells regulated by IL-6 signal is involved in superantigen-mediated CD4(+) T cell death
Toru Atsumi, Masae Sato, Daisuke Kamimura, Arisa Moroi, Yoichiro Iwakura, Ulrich A. K. Betz, Akihiko Yoshimura, Mika Nishihara, Toshio Hirano, Masaaki Murakami, INTERNATIONAL IMMUNOLOGY, 21, 1, 73, 80, Jan. 2009
English - Liver as a regulator of T cells
2009 - Zinc prevents Th17 cell-mediated autoimmune disease by directly inhibiting STAT3
2009 - 関節局所でのIL-6 amplify loopの活性化がF759関節炎発症には重要である
2009 - The recognition of specific antigens is not always required for the development of tissue-specific autoimmune diseases associated with MHC II.
2009 - Foxp3+CD8+ T cells inhibit the development of F759 arthritis.
2009 - 亜鉛シグナルの標的分子の探索と解析
2009 - Zinc prevents Th17 cell-mediated autoimmune disease by directly inhibiting STAT3
2009 - Foxp3+CD8+ T cells inhibit the development of F759 arthritis.
2009 - Impaired STAT activations in an ENU mutant mouse carrying excess memory T cells
2009 - IFN-gamma expression in CD8(+) T cells regulated by IL-6 signal is involved in superantigen-mediated CD4(+) T cell death
Toru Atsumi, Masae Sato, Daisuke Kamimura, Arisa Moroi, Yoichiro Iwakura, Ulrich A. K. Betz, Akihiko Yoshimura, Mika Nishihara, Toshio Hirano, Masaaki Murakami, INTERNATIONAL IMMUNOLOGY, 21, 1, 73, 80, Jan. 2009
English - Liver as a regulator of T cells
2009 - IL-6アンプと炎症性疾患
細胞工学, 28(11):1107-1112, 2009, 2009 - Metallothionein I/II分子によるCD4+T細胞依存性の自己免疫疾患の抑制機序
2009 - Hepatic IL-7 Regulates CD4+T Cell-mediated Autoimmune diseases.
2009 - c-Cbl-dependent monoubiquitination and lysosomal degradation of gp130
Yoshinori Tanaka, Nobuyuki Tanaka, Yasushi Saeki, Keiji Tanaka, Masaaki Murakami, Toshio Hirano, Naoto Ishii, Kazuo Sugamura, MOLECULAR AND CELLULAR BIOLOGY, 28, 15, 4805, 4818, Aug. 2008
English - Combination treatment with IL-2 and anti-IL-2 mAbs reduces tumor metastasis via NK cell activation
Gui-Hua Jin, Toshio Hirano, Masaaki Murakami, INTERNATIONAL IMMUNOLOGY, 20, 6, 783, 789, Jun. 2008
English - Roles of zinc in intracellular signal transduction
村上 正晃, 平野 俊夫, Cell technology., 27, 3, 237, 241, Mar. 2008
秀潤社, Japanese - Dysregulation of an IL-17-Triggered Positive Feedback Loop of IL-6 Signaling in an Autoimmune Arthritis.
Immunity, 29: 628-636, 2008 - Roles of zinc and zinc signaling in immunity: Zinc as an intracellular signaling molecule
Toshio Hirano, Masaaki Murakami, Toshiyuki Fukada, Keigo Nishida, Satoru Yamasaki, Tomoyuki Suzuki, ADVANCES IN IMMUNOLOGY, VOL 97, 97, 149, 176, 2008
English - Intracellular Zinc homeostasis and Zinc signaling.
Cancer Science, 99:1515-22, 2008 - Intracellular Zinc homeostasis and Zinc signaling.
Cancer Science, 99:1515-22, 2008 - Dysregulation of an IL-17-Triggered Positive Feedback Loop of IL-6 Signaling in an Autoimmune Arthritis.
Immunity, 29: 628-636, 2008 - Th17 differentiation and cytokine signaling
奥山 祐子, 村上 正晃, Clinical immunology & allergology, 48, 4, 347, 353, Oct. 2007
科学評論社, Japanese - IL-6-gp130-STAT3 in T cells directs the development of IL-17+T-h with a minimum effect on that of Treg in the steady state
Mika Nishihara, Hideki Ogura, Naoko Ueda, Mineko Tsuruoka, Chika Kitabayashi, Fumio Tsuji, Hiroyuki Aono, Katsuhiko Ishihara, Eric Huseby, Ulrich A. K. Betz, Masaaki Murakami, Toshio Hirano, INTERNATIONAL IMMUNOLOGY, 19, 6, 695, 702, Jun. 2007
English - Regulation of MHC class 2 by IL-6
北村 秀光, 村上 正晃, Clinical immunology & allergology, 47, 2, 157, 163, Feb. 2007
科学評論社, Japanese - Verella-Garcia, J. Kappler, P. Marrack, and T. Hirano. Homeostatic proliferating CD4 T cells are involved in the pathogenesis of an Omenn syndrome murine model.
J. Clin. Invest., 17: 1270-1281, 2007 - Guihua Jin, Masaaki Murakami, and Toshio Hirano
2007 - IL-6 inhibits PLCg activation in TCR-mediated signaling
2007 - Guihua Jin, Masaaki Murakami, and Toshio Hirano
2007 - Verella-Garcia, J. Kappler, P. Marrack, and T. Hirano. Homeostatic proliferating CD4 T cells are involved in the pathogenesis of an Omenn syndrome murine model.
J. Clin. Invest., 17: 1270-1281, 2007 - Antigen independent induction of a CD4+ T cell-dependent arthritis.
2007 - IL-6 inhibits PLCg activation in TCR-mediated signaling
2007 - Antigen independent induction of a CD4+ T cell-dependent arthritis.
2007 - Liver acute-phase reactions convert innate immune signaling into adaptive immune responses
2007 - Liver acute-phase reactions convert innate immune signaling into adaptive immune responses
2007 - The point mutation of tyrosine 759 of the IL-6 family cytokine receptor gp130 augments collagen-induced arthritis in DBA/1J mice.
Fumio Tsuji, Hiroyuki Aono, Miwa Yoshimi, Osamu Katsuta, Miwa Takai, Masaaki Murakami, Toshio Hirano, Katsuhiko Ishihara, ARTHRITIS AND RHEUMATISM, 54, 9, S174, S174, Sep. 2006
English, Summary international conference - Toll-like receptor-mediated regulation of zinc homeostasis influences dendritic cell function
Hidemitsu Kitamura, Hideyuki Morikawa, Hokuto Kamon, Megumi Iguchi, Shintaro Hojyo, Toshiyuki Fukada, Susumu Yamashita, Tsuneyasu Kaisho, Shizuo Akira, Masaaki Murakami, Toshio Hirano, NATURE IMMUNOLOGY, 7, 9, 971, 977, Sep. 2006
English - CD1d-restricted NKT cell activation enhanced homeostatic proliferation of CD8(+) T cells in a manner dependent on IL-4
Naoko Ueda, Hiroko Kuki, Daisuke Kamimura, Shinichiro Sawa, Kenichiro Seino, Takuya Tashiro, Ken-ichi Fushuku, Masaru Taniguchi, Toshio Hirano, Masaaki Murakami, INTERNATIONAL IMMUNOLOGY, 18, 9, 1397, 1404, Sep. 2006
English - IL-6-STAT3信号伝達系による樹状細胞の機能制御 (特集1 樹状細胞とT細胞の相互作用)
北村 秀光, 村上 正晃, 臨床免疫・アレルギー科, 46, 2, 141, 147, Aug. 2006
科学評論社, Japanese - IL-2 in vivo activities and antitumor efficacy enhanced by an anti-IL-2 mAb
D Kamimura, Y Sawa, M Sato, E Agung, T Hirano, M Murakami, JOURNAL OF IMMUNOLOGY, 177, 1, 306, 314, Jul. 2006
English - Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic proliferation of CD4(+) T cells
S Sawa, D Kamimura, GH Jin, H Morikawa, H Kamon, M Nishihara, K Ishihara, M Murakami, T Hirano, JOURNAL OF EXPERIMENTAL MEDICINE, 203, 6, 1459, 1470, Jun. 2006
English - Grasp a pTyr-peptide by its SOCS
T Hirano, M Murakami, DEVELOPMENTAL CELL, 10, 5, 542, 544, May 2006
English, Others - Grasp a pTyr-peptide by its SOCS.
Dev. Cell, 10:542-544, 2006 - IL-6-STAT3 controls intracellular MHC class II alpha beta dimer level through cathepsin S activity in dendritic cells
H Kitamura, H Kamon, SI Sawa, SJ Park, N Katunuma, K Ishihara, M Murakami, T Hirano, IMMUNITY, 23, 5, 491, 502, Nov. 2005
English - gp130シグナルの異常とリウマチ様関節炎
澤新一郎, 村上正晃, 実験医学(増刊), 23, 11, 224, 229, 2005, [Invited]
Japanese, Introduction commerce magazine - IL-12関連サイトカインIL-27のシグナル伝達機構
浅川 正幸, 森島 紀子, 大脇 敏之, 村上 正晃, 平野 俊夫, 水口 純一郎, 善本 隆之, 日本免疫学会総会・学術集会記録, 34, 126, 126, Nov. 2004
(NPO)日本免疫学会, Japanese - VEGFR-1 (Fit-1) tyrosine kinase signaling enhances hematopoiesis, proliferation/differentiation and immunity of monocyte/macrophage from bone marrow hematopoietic stem cells, and promotes rheumatoid arthritis
M Murakami, S Iwai, S Hirasuka, Y Iwakura, Y Maru, M Shibuya, BLOOD, 104, 11, 223A, 223A, Nov. 2004
English, Summary international conference - Tyrosine dephosphorylation of STAT3 in SARS coronavirus-infected Vero E6 cells
T Mizutani, S Fukushi, M Murakami, T Hirano, M Saijo, Kurane, I, S Morikawa, FEBS LETTERS, 577, 1-2, 187, 192, Nov. 2004
English - Evidence of a novel IL-2/15R beta-targeted cytokine involved in homeostatic proliferation of memory CD8(+) T cells
D Kamimura, N Ueda, Y Sawa, S Hachida, T Atsumi, T Nakagawa, SI Sawa, GH Jin, H Suzuki, K Ishihara, M Murakami, T Hirano, JOURNAL OF IMMUNOLOGY, 173, 10, 6041, 6049, Nov. 2004
English - IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation
SJ Park, T Nakagawa, H Kitamura, T Atsumi, H Kamon, S Sawa, D Kamimura, N Ueda, Y Iwakura, K Ishihara, M Murakami, T Hirano, JOURNAL OF IMMUNOLOGY, 173, 6, 3844, 3854, Sep. 2004
English - New IL-6 (gp130) family cytokine members, CLC/NNT1/BSF3 and IL-27.
Growth Factors., 22, 75-7., 2004 - New IL-6 (gp130) family cytokine members, CLC/NNT1/BSF3 and IL-27.
Growth Factors., 22, 75-7./,, 2004 - Development of Atherosclerosis in Osteopontin Transgenic Mice
Chiba Satoru, Okamoto Hiroshi, Akino Masatoshi, Jia Nan, Sugawara Takeshi, Shimizu Toshihiro, Matsui Yutaka, Kitabatake Akira, Murakami Masaaki, Uede Toshimitsu, Circulation journal : official journal of the Japanese Circulation Society, 66, 144, 144, 31 Mar. 2002
Japanese Circulation Society, English - Single molecule imaging of H-Ras activation in living cells
M Murakami, T Kobayashi, C Ohshima, H Murakoshi, M Sakuma, Y Takeda, R Iino, S Minoguchi, A Yoshimura, A Kusumi, MOLECULAR BIOLOGY OF THE CELL, 12, 402A, 402A, Nov. 2001
English, Summary international conference - (2)トランスジェニックマウスを用いたデキサメサゾン誘導胸腺細胞アポトーシスにおけるDIG1遺伝子の機能解析(第20回日本胸腺研究会)
土佐 紀子, 岩田 誠, 横山 峯介, 岩渕 和也, 猪部 学, 村上 正晃, 上出 利光, 日本呼吸器外科学会雑誌, 15, 5, 1a, 2a, 15 Jul. 2001
特定非営利活動法人日本呼吸器外科学会, Japanese - SF7a-1 CD40Ig及びCTLA4Ig遺伝子組込みアデノウイルスベクターを併用した新しい遺伝子治療によるラット移植心の長期生着
山下 健一郎, 柳田 尚之, 竹原 めぐみ, 小林 篤寿, 越前谷 勇人, 野村 克, 砂原 正男, 北河 徳彦, 崎浜 秀康, 村上 正晃, 古川 博之, 上出 利光, 藤堂 省, 日本外科学会雑誌, 102, 0, 92, 92, 10 Mar. 2001
一般社団法人日本外科学会, Japanese - Functional analysis of HVEM, a member of TNFR family, by using a transgenic mice expressing soluble form of HVEM
M Inobe, T Uenishi, M Murakami, T Uede, FASEB JOURNAL, 15, 4, A352, A352, Mar. 2001
English, Summary international conference - The functional analysis of DIG1 molecule, a putative G protein-coupled receptor, in dexamethasone-induced thymocyte apoptosis.
N Tosa, M Murakami, M Iwata, WY Jia, M Yokoyama, K Iwabuchi, M Inobe, T Uede, FASEB JOURNAL, 15, 4, A315, A315, Mar. 2001
English, Summary international conference - Homeostasis of alpha beta TCR+ T cells
P Marrack, J Bender, D Hildeman, M Jordan, T Mitchell, M Murakami, A Sakamoto, BC Schaefer, B Swanson, J Kappler, NATURE IMMUNOLOGY, 1, 2, 107, 111, Aug. 2000
English, Book review - CTLA4IgG gene delivery prevents autoantibody production and lupus nephritis in MRL/lpr mice
M Takiguchi, M Murakami, Nakagawa, I, A Hashimoto, T Uede, FASEB JOURNAL, 14, 6, A1207, A1207, Apr. 2000
English, Summary international conference - Maintenance of memory CD8+T cells is dependent upon a balance of IL-2 family cytokines.
M Murakami, CC Ku, A Sakamoto, J Kappler, P Marrack, FASEB JOURNAL, 14, 6, A989, A989, Apr. 2000
English, Summary international conference - Combination therapy of CTLA4IG and FTY720 completely prevent the development of obliterative bronchiolitis and respiratory epitherial injury in a murine airway model.
K Konishi, M Murakami, M Inobe, A Yamada, H Echizenya, K Yamashita, M Nomura, T Omura, S Todo, T Uede, TRANSPLANTATION, 69, 8, S301, S301, Apr. 2000
English, Summary international conference - Long term liver graft acceptance with an novel adenovirus mediated CD40IgG gene transfer on rat.
M Nomura, K Yamashita, M Murakami, M Takehara, K Konishi, H Echizenya, N Yanagida, Z Xu-Dong, T Omura, A Kishida, H Furukawa, T Uede, S Todo, TRANSPLANTATION, 69, 8, S279, S279, Apr. 2000
English, Summary international conference - JAK 2 is associated with a box 1 like motif and phospholylates a critical tyrosine residue in the cytoplasmic region of CTLA-4.
S Chikuma, M Murakami, M Inobe, T Uede, FASEB JOURNAL, 14, 6, A1178, A1178, Apr. 2000
English, Summary international conference - Immunotherapy of Osteosarcoma Using B7-1-transfected Tumor Vaccine in Rat Orthotopic Implantation Model
KAWAGUCHI T., 日本整形外科學會雜誌, 74, 3, S680, 25 Mar. 2000
Japanese - SF7a-4 CTLA4Ig及びFTY720の慢性拒絶反応の抑制効果
小西 勝人, 村上 正晃, 野村 克, 山下 健一郎, 柳田 尚之, 越前谷 勇人, 竹原 めぐみ, 大村 孝志, 古川 博之, 岸田 明博, 上出 利光, 藤堂 省, 日本外科学会雑誌, 101, 0, 122, 122, 10 Mar. 2000
一般社団法人日本外科学会, Japanese - Blocking the CD28-B7 T-cell costimulatory pathway abrogates the development of obliterative bronchiolitis in a murine heterotopic airway model
A Yamada, K Konishi, GLE Cruz, M Takehara, M Morikawa, Nakagawa, I, M Murakami, T Abe, S Todo, T Uede, TRANSPLANTATION, 69, 5, 743, 749, Mar. 2000
English - 好中球はオステオポンチン産生能を有する
上野 博史, 村上 正晃, 奥村 正裕, 廉沢 剛, 上出 利光, 藤永 徹, 日本獣医学会学術集会講演要旨集, 129回, 140, 140, Mar. 2000
(公社)日本獣医学会, Japanese - Adenovirus vectorを用いたオステオポンチン発現系の樹立
RASHID M M, 猪部学, 今重之, 村上正晃, 上出利光, 日本免疫学会総会・学術集会記録, 30, 2000 - 肝炎遷延化におけるTh1/Th2レギュレーター,オステオポンチンの役割
猪部学, 村上正晃, 今重之, 上出利光, 日本免疫学会総会・学術集会記録, 30, 2000 - Control of homeostasis of CD8+ memory T cells by opposing cytokines
KU CC, Science, 288, 5466, 675, 678, 2000 - Osteopontin exacerbates atherosclerotic lesions in transgenic mice
S Chiba, H Okamoto, Y Matsui, T Shimizu, K Kumamoto, M Watanabe, M Murakami, T Uede, A Kitabatake, CIRCULATION, 100, 18, 696, 696, Nov. 1999
English, Summary international conference - CTLA4IgG発現アデノウイルスベクターを用いたループス腎炎への遺伝子治療の試み
TAKIGUCHI MITSUYOSHI, MURAKAMI MASAAKI, NAKAGAWA IZUMI, SAITO IZUMI, HASHIMOTO AKIRA, KAMIDE TOSHIMITSU, 日本獣医学会学術集会講演要旨集, 128th, 20, 20, 01 Sep. 1999
(公社)日本獣医学会, Japanese - Combination of CTLA41GG and FTY720 suppresses development of obliterative bronchiolitis and respiratory epithelial injury in a murine heterotopic airway model
K Konishi, M Murakami, A Yamada, M Takiguchi, M Morikawa, T Omura, S Todo, T Uede, TRANSPLANTATION, 67, 9, S605, S605, May 1999
English, Summary international conference - MRL/lprマウス肺病変形成におけるCD28/CTLA4‐B7補助シグナルの役割
TAKIGUCHI MITSUNOBU, MURAKAMI MASAAKI, NAKAGAWA IZUMI, YASUDA JUN, HASHIMOTO AKIRA, KAMIDE TOSHIMITSU, 日本獣医学会学術集会講演要旨集, 127th, 68, 68, 01 Mar. 1999
(公社)日本獣医学会, Japanese - P782 オステオポンチントランスジェニックマウスにおける動脈硬化の促進
千葉 知, 岡本 洋, 松井 裕, 清水 紀宏, 熊本 秀樹, 中川 泉, 渡邊 正司, 米谷 圭史, 小野塚 久夫, 三神 大世, 北畠 顕, 村上 正晃, 上出 利光, Japanese circulation journal, 63, 1, 646, 646, 01 Mar. 1999
社団法人日本循環器学会, Japanese - O-483 CTLA4IgG発現アデノウィルスベクターのCre/loxPによる発現制御
竹原 めぐみ, 村上 正晃, 中川 泉, 小西 勝人, 野村 克, 柳田 尚之, 大村 孝志, 古川 博之, 岸田 明博, 鐘ケ江 裕美, 斉藤 泉, 上出 利光, 藤堂 省, 日本外科学会雑誌, 100, 228, 228, 10 Feb. 1999
一般社団法人日本外科学会, Japanese - Effects of a novel immunosuppressant, FTY720, on heart and liver transplantations in rats
K. Yamashita, M. Nomura, T. Omura, M. Takehara, T. Suzuki, T. Shimamura, A. Kishida, H. Furukawa, M. Murakami, T. Uede, S. Todo, Transplantation Proceedings, 31, 1-2, 1178, 1179, Feb. 1999
English - オステオポンチンの過剰発現による肉芽腫性肺病変の出現
千葉知, 村上正晃, RASHID M M, 白岩宙丈, 今重之, 猪部学, 岡本洋, 北畠顕, 上出利光, 日本免疫学会総会・学術集会記録, 29, 1999 - Persistent and secondary gene expression on using Adex1CACTLA4IgG
MURAKAMI Masaaki, NAKAGAWA Izumi, ISHIKURA Hiroshi, KANEGAE Yumi, SAITO Izumi, UEDE Toshimitsu, 日本分子生物学会年会プログラム・講演要旨集, 21, 590, 590, 01 Dec. 1998
Japanese - Control of CTLA4IgG expression from adenovirus vector using Cre/loxP system
TAKEHARA Megumi, MURAKAMI Masaaki, NAKAGAWA Izumi, KANEGAE Yumi, SAITO Izumi, TODO Satoru, UEDE Toshimitsu, 日本分子生物学会年会プログラム・講演要旨集, 21, 591, 591, 01 Dec. 1998
Japanese - 1prマウス肺病変形成におけるCD28/CTLA4-B7補助シグナルの役割
滝口 満喜, 村上 正晃, 中川 泉, 橋本 晃, 上出 利光, 日本臨床免疫学会会誌, 26回抄録集, 376, 376, Oct. 1998
(一社)日本臨床免疫学会, Japanese - CTLA4Ig overexpression enables secondary adenovirus administration and prolongs adenovirus-mediated gene transfer
Nakagawa, I, H Okamoto, S Chiba, H Kumamato, K Yoneya, M Watanabe, M Murakami, T Uede, CIRCULATION, 98, 17, 796, 796, Oct. 1998
English, Summary international conference - Adenovirus-mediated gene transfer of CTLA4Ig is highly efficient and prolongs cardiac allograft survival
Nakagawa, I, H Okamoto, S Chiba, H Kumamato, K Yoneya, M Watanabe, M Murakami, T Uede, CIRCULATION, 98, 17, 399, 399, Oct. 1998
English, Summary international conference - lprマウス肺病変形成におけるCD28/CTLA4‐B7補助シグナルの役割
TAKIGUCHI MITSUYOSHI, MURAKAMI MASAAKI, NAKAGAWA IZUMI, HASHIMOTO AKIRA, UEDE TOSHIMITSU, 日本免疫学会総会・学術集会記録, 28, 376, Oct. 1998
Japanese - Persistent and secondary adenovirus-mediated hepatic gene expression using adenovirus vector containing CTLA4IgG
Izumi Nakagawa, Masaaki Murakami, Kenichi Ijima, Shunsuke Chikuma, Izumu Saito, Yumi Kanegae, Hiroshi Ishikura, Takashi Yoshiki, Hiroshi Okamoto, Akira Kitabatake, Toshimitsu Uede, Human Gene Therapy, 9, 12, 1739, 1745, 10 Aug. 1998
Mary Ann Liebert Inc., English, Book review - Concern of CD28/CTLA4-B7 support signal in pathogeny of MRL/lpr mouse.
TAKIGUCHI MITSUYOSHI, MURAKAMI MASAAKI, NAKAGAWA IZUMI, YASUDA JUN, HASHIMOTO AKIRA, KAMIIDE TOSHIMITSU, 日本獣医学会学術集会講演要旨集, 126th, 22, 22, Aug. 1998
(公社)日本獣医学会, Japanese - Blockade of CD28/CTLA4 pathway prevented almost diseases and lymphadenopathy but not lung disease in MRL/lpr mice.
M Takiguchi, M Murakami, Nakagawa, I, A Yamada, S Chikuma, T Uede, FASEB JOURNAL, 12, 5, A1093, A1093, Mar. 1998
English, Summary international conference - イヌの脳性ナトリウム利尿ペプチド遺伝子のクローニング
浅野 和之, 村上 正晃, 遠藤 大二, 木村 享史, 奥村 正裕, 廉澤 剛, 藤永 徹, 日本獣医学会学術集会講演要旨集, 125回, 267, 267, Mar. 1998
(公社)日本獣医学会, Japanese - キチン・キトサンのマウス常在腹腔マクロファージに対する作用
森 崇, 村上 正晃, 上出 利光, 蒲 直樹, 田中 一郎, 奥村 正裕, 廉澤 剛, 藤永 徹, 日本獣医学会学術集会講演要旨集, 125回, 275, 275, Mar. 1998
(公社)日本獣医学会, Japanese - The functional role of B7 molecules on the induction of thymocyte activation and apoptosis.
Naoko Aoki, Manabu Inobe, Masaaki Murakami, Ryo Abe, Hajime Iizuka, Collected papers from the Institute of Immunological Science Hokkaido University, 21, 281, 291, 1998
Hokkaido University, English - Expression and costimulatory function of B7-2 on murine CD4+ T cells.
Rie Hakamada-Taguchi, Takuma Kato, Hiroshi Ushijima, Masaaki Murakami, Toshimitsu Uede, Hideo Nariuchi, Collected papers from the Institute of Immunological Science Hokkaido University, 21, 301, 309, 1998
Hokkaido University, English - The mechanism by which proteolysis enhances the ligand binding activity of guinea pig typeII Fc receptor for IgG (FcγRIIB).
Yasuhiro Isashi, Toshiyuki Yamashita, Shigeharu Nagasawa, Kumiko Tanaka, Masaaki Murakami, Toshimitsu Uede, Collected papers from the Institute of Immunological Science Hokkaido University, 21, 292, 300, 1998
Hokkaido University, English - Selective antigen presenting activity of cortical thymic epithelial cells against CD4+ T cells associated with both lack of costimulatory molecules and inefficient presentation of MHC-peptide ligands
Rika Kaneda, Kazuya Iwabuchi, Michiyuki Kasai, Masaaki Murakami, Toshimitu Uede, Kazunori Onoé, Cellular Immunology, 181, 2, 163, 171, 01 Nov. 1997
Academic Press Inc., English - CD80 combination activity shown by a phage library clone to combine with the anti-CTLA4 antibody.
鳥越直彦, 福元隆浩, 川畑慎一, 米田明広, 村上正晃, 上出利光, 西徹, 伊東祐二, 杉村和久, 日本免疫学会総会・学術集会記録, 27, 199, Oct. 1997
Japanese - Immunoregulation activity of phage library clone combining with anti-CTLA4 antibody.
福元隆浩, 鳥越直彦, 川畑慎一, 村上正晃, 上出利光, 西徹, 伊東祐二, 杉村和久, 日本免疫学会総会・学術集会記録, 27, 139, Oct. 1997
Japanese - Analysis of a peptide motif to combine with the anti-CD86 antibody using the phage library.
米田明広, 鳥越直彦, 福元隆浩, 川畑慎一, 村上正晃, 上出利光, 西徹, 伊東祐二, 杉村和久, 日本免疫学会総会・学術集会記録, 27, 199, Oct. 1997
Japanese - Anti Tumor Immunity of B7-1 or B7-2 Induced Mouse Osteosarcoma Cells
NAGAMORI M., 日本整形外科學會雜誌 = The Journal of the Japanese Orthopaedic Association, 71, 8, S1368, 25 Aug. 1997
Japanese - B細胞上のCD28/CTLA-4結合分子ACBM (リンパ球表面分子と免疫調節)
村上 正晃, 高橋 陽子, 今 重之, 免疫, 1997, 106, 111, Aug. 1997
中山書店, Japanese - CD28,CTLA4/B7-1,B7-2とclonal anergy (特集 寛容導入をめざす移植免疫学)
村上 正晃, 山田 陽, 上出 利光, モレキュラ-メディシン, 34, 7, 842, 853, Jul. 1997
中山書店, Japanese - Osteopontin, a coordinator of host defense system: a cytokine or an extracellular adhesive protein?
T Uede, Y Katagiri, J Iizuka, M Murakami, MICROBIOLOGY AND IMMUNOLOGY, 41, 9, 641, 648, 1997
English, Book review - Identification of an alternative CTLA4 ligand on mouse B cells.
M Murakami, Y Takahashi, Y Isashi, N Aoki, S Kon, WY Jia, M Inobe, R Abe, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 99, 1, 886, 886, Jan. 1997
English, Summary international conference - Limb Allografts in Rats Enhance the Survival of Skin Allografts
TSUCHIDA Y., 日本整形外科學會雜誌 = The Journal of the Japanese Orthopaedic Association, 70, 8, S1539, 25 Aug. 1996
Japanese - 炎症部位における好中球Fc_γRの活性化機構
山下 俊之, 井指 康裕, 長澤 滋治, 村上 正晃, 上出 利光, 日本分子生物学会年会プログラム・講演要旨集, 19, 20, 20, Aug. 1996
Japanese - 静止期のB細胞に発現する新しいCD28, CTLA4結合分子, ACBMの同定とその機能
村上 正晃, 上出 利光, 日本分子生物学会年会プログラム・講演要旨集, 19, 20, 20, Aug. 1996
Japanese - Activation of JNK and ERK2 by CD40-mediated signals in WEHI231 cells.
T Hara, M Murakami, M Hibi, T Uede, FASEB JOURNAL, 10, 6, 395, 395, Apr. 1996
English, Summary international conference - The role of B7-1a molecule, an alternatively spliced form of murine B7-1(CD80), on T cell activation.
Manabu Inobe, Naoko Aoki, Peter S. Linsley, Jeffrey A. Ledbetter, Ryo Abe, Masaaki Murakami, Toshimitsu Uede, Collected papers from the Institute of Immunological Science Hokkaido University, 19, 292, 298, 1996
Hokkaido University, English - Identification and characterization of an alternative cytotoxic Tlymphocyte-associated protein 4 binding molecule on B cells.
Masaaki Murakami, Yohko Takahashi, Yasuhiro Isashi, Shigeyuki Kon, Wen-Yi Gia, Manabu Inobe, Ryo Abe, Toshimitsu Uede, Collected papers from the Institute of Immunological Science Hokkaido University, 19, 287, 291, 1996
Hokkaido University, English - Vaccination of tumor cells transfected with B7-1 (CD80) gene Induces the'anti-metastatic effect and tumor immunity in mice.
Hideki Fujii, Manabu Inobe, Fuminari Kimura, Jun Murata, Masaaki Murakami, Yasuharu Onishi, Ichiro Azuma, Toshimitsu Uede, Ikuo Saiki., Collected papers from the Institute of Immunological Science Hokkaido University, 19, 160, 165, 1996
Hokkaido University, English - Long-term acceptance of major histocompatibility complex- mismached cardiac allograft induced by a low does of CTLA4IgM plus FK506.
Akira Yamada, Masaaki Murakami, Kenichi Ijima, Hideo Yagita, Yagita, Kou Okumura, Sakuzo Komatsu, Toshimitsu Uede, Collected papers from the Institute of Immunological Science Hokkaido University, 19, 281, 286, 1996
Hokkaido University, English - Analysis of appearance of ACBM, a new CTLA4 combination molecule to appear in a B cell, in a mouse in vivo.
高橋陽子, 青木直子, 今重之, 村上正晃, 上出利光, 日本免疫学会総会・学術集会記録, 26, 1996 - Analysis of combination region on CTLA-4 for ACBM, a new CTLA-4 combining molecule.
今重之, 高橋陽子, 青木直子, 村上正晃, 上出利光, 日本免疫学会総会・学術集会記録, 26, 1996 - Isolation of DIG-1 gene induced dexamethasone dependently and thymus gland specifically.
こ文い, 今重之, 村上正晃, 上出利光, 日本免疫学会総会・学術集会記録, 26, 1996 - Analysis of the CD40 signal transfer mechanism.
原豊道, 今重之, 村上正晃, 上出利光, 日本免疫学会総会・学術集会記録, 26, 1996 - Identification of ACBM, a new combined molecule of CD28 and CTLA4 to appear in a B cell, and its function.
村上正晃, 高橋陽子, 井指康裕, 今重之, か文い, 猪部学, 阿部良, 上出利光, 日本免疫学会総会・学術集会記録, 26, 1996 - ANGIOTENSIN-CONVERTING ENZYME GENE POLYMORPHISM IN JAPANESE PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY
K YONEYA, H OKAMOTO, M MACHIDA, H ONOZUKA, M NOGUCHI, T MIKAMI, H KAWAGUCHI, M MURAKAMI, T UEDE, A KITABATAKE, AMERICAN HEART JOURNAL, 130, 5, 1089, 1093, Nov. 1995
English - Functional analysis of the osteopontin molecule
Katagiri Yohko, Mori Kiyoshi, Hara Toyomichi, Tanaka Kumiko, Murakami Masaaki, Uede Toshimitsu, Collected papers from the Institute of Immunological Science Hokkaido University, 18, 317, 320, 1995
Hokkaido University, English - IDENTIFICATION OF ALTERNATIVELY SPLICED FORM OF THE MURINE B7 HAVING ALTERED RECEPTOR-BINDING AND FUNCTIONAL-PROPERTIES
M INOBE, M MURAKAMI, Y NAGAI, PS LINSLEY, JA LEDBETTER, T UEDE, FASEB JOURNAL, 8, 5, A1014, A1014, Mar. 1994
English, Summary international conference - THE ROLL OF COSTIMULATORY SIGNALS IN PROLIFERATION OF DOUBLE-NEGATIVE (DN) T-CELLS OF LPR MICE
Y NAGAI, M INOBE, M MURAKAMI, T UEDE, FASEB JOURNAL, 8, 5, A1002, A1002, Mar. 1994
English, Summary international conference
Lectures, oral presentations, etc.
- 血液脳関門への免疫細胞の侵入口の形成—炎症アンプのヒト病気への関連と定常時の機能
村上 正晃
第13回神経-筋の免疫疾患を考える会, 2013, Invited oral presentation
[Invited] - EAE investigation by using the ultra-high field MRI.
Masaaki Murakami
Osaka University Live Immuno-Imaging Facility Opening workshop, 2013, Nominated symposium
[Invited] - How is a gateway of immune cells created in the brain-blood barrier?
Masaaki Murakami
Neuro2013, 2013, English, Nominated symposium
[Invited], [International presentation] - A gravity-mediated gateway for autoreactive CD4+ T cells in the brain-blood barrier.
Masaaki Murakami
34th International Society for Gravitational Physiology, 2013, English, Nominated symposium
[Invited], [International presentation] - 炎症アンプによる病気、病態の制御
村上 正晃
次世代重点研究プログラムセミナー, 2013, Invited oral presentation
[Invited] - 炎症の慢性化機構の解明と制御
村上 正晃
第18回日本病態プロテアーゼ学会学術集会, 2013, Nominated symposium
[Invited] - 慢性炎症の誘導機構”炎症アンプ”の活性化と病態形成
村上 正晃
第６回Symphony, 2013, Nominated symposium
[Invited] - 炎症アンプの活性化と関節炎の発症
村上 正晃
小児リウマチ学会, 2013, Nominated symposium
[Invited], [Domestic Conference] - 炎症の慢性化誘導機構『IL-6アンプ』と関節炎
村上 正晃
第56回日本リウマチ学会学術集会, 2012, Invited oral presentation
[Invited] - 神経刺激による血液脳関門の血管の制御：自己反応性T細胞の侵入口の形成
村上 正晃
第46回北摂循環器研究会, 2012, Invited oral presentation
[Invited] - 非免疫細胞に存在する炎症誘導機構、 IL-6アンプ
村上 正晃
北海道大学遺伝子病制御研究所セミナー, 2012, Public discourse
[Invited] - 神経刺激による血液脳関門への免疫細胞の侵入口の形成
村上 正晃
第22回サイトメトリー学会学術集会, 2012, Invited oral presentation
[Invited] - 局所の神経活性化による病原性T細胞の中枢移行メカニズム
村上 正晃
病態に根ざしたALSの新規治療法開発分科班ワークショップ, 2012, Nominated symposium
[Invited] - 局所の神経活性化による自己免疫病の制御
村上 正晃
名古屋大学大学院医学系研究科GCOEニューロサイエンスコースセミナー, 2012, Public discourse
[Invited] - IL-6アンプと慢性炎症
村上 正晃
第27回日本整形外科学会基礎学術集会, 2012, Nominated symposium
[Invited], [Domestic Conference] - 病原T細胞の中枢神経系への侵入口の形成メカニズム—非免疫細胞の炎症誘導機構“IL-6アンプ”の役割—
村上 正晃
北海道大学獣医学研究科学術交流基金群講演, 2012, Public discourse
[Invited] - 重力刺激による中枢神経系への免疫細胞侵入口の形成
村上 正晃
第58回日本宇宙航空環境医学会, 2012, Invited oral presentation
[Invited], [Domestic Conference] - 活性化T細胞と中枢神経系の病気、病態
村上 正晃
第41回日本免疫学会学術集会, 2012, Invited oral presentation
[Invited], [Domestic Conference] - Local neural pathway and a gateway for pathogenic T cells in the CNS
Masaaki Murakami
2012 Annual Meeting of the Japanese Society for Immunology, 2012, Nominated symposium
[Invited], [International presentation] - Regional neural activation defines a gateway in the blood brain barrier for immune cells
Masaaki Murakami
IFReC-SIgN Winter School, 2012, English, Invited oral presentation
[Invited], [Domestic Conference] - サイトカインと慢性炎症—“IL-6アンプ”の役割
村上 正晃
富山大学大学院医学薬学研究部特別セミナー・特別講演, 2012, Invited oral presentation
[Invited], [Domestic Conference] - 血液脳関門への免疫細胞の侵入口の形成と自己免疫疾患
村上 正晃
第12回東北大学がん・エピゲノム研究会, 2012
[Invited] - 中枢神経系への免疫細胞の侵入メカニズム
村上 正晃
第40回日本臨床免疫学会総会・シンポジウム, 2012
[Invited], [Domestic Conference] - 免疫細胞の中枢神経系への侵入口と仕組みについて
村上 正晃
第17回グリア研究会・招待セミナー, 2012
[Invited] - IL-17A-triggered positive-feedback for IL-6-signaling, a key player for inflammation, is associated with various human diseases.
Masaaki Murakami
RCAI-CGM Joint Meeting, 2011, Invited oral presentation
[Invited], [Domestic Conference] - Inflammation and Zinc signaling.
Masaaki Murakami
The 5th International Conference on Metals and Genetics, 2011, English, Invited oral presentation
[Invited], [International presentation] - The IL-6 amplifier activation, a key player of inflammation, in human diseases and disorders.
Masaaki Murakami
Annual Meeting of the Japanese Society for Immunology・International symposium, 2011, English, Invited oral presentation
[Invited], [International presentation] - Zinc and CD4+ T cell-mediated autoimmune diseases.
Masaaki Murakami
The 60th Fujihara Seminar Zinc Signaling and Cellular Functions, 2010, English, Invited oral presentation
[Invited], [International presentation] - How does IL-17 induce Autoimmune Diseases?
Masaaki Murakami
The 2nd International Symposium of WPI-IFReC, 2009, English, Invited oral presentation
[Invited], [International presentation] - Liver as a regulator of T cells.
Masaaki Murakami
The 5th International Workshop of Kyoto T Cell Conference 2009, 2009, English, Invited oral presentation
[Invited], [International presentation] - Is the recognition of cognate antigens always required for the determination of the tissue specificity of autoimmune diseases associated with MHC II?”
Masaaki Murakami
Annual Meeting of the Japanese Society for Immunology, 2009, English, Invited oral presentation
[Invited], [International presentation] - 抗原提示におけるサイトカインとカテプシンの関係
村上 正晃
徳島文理大学・健康科学研究所・私学助成研究発表会, 2008, Invited oral presentation
[Invited] - Foxp3+抑制性CD8+ T細胞による免疫反応の制御
村上 正晃
第18回日本サイトメトリー学会学術総会, 2008, Invited oral presentation
[Invited], [Domestic Conference] - 細胞内亜鉛信号による細胞活性化の制御
村上 正晃
日本薬学会第128回年会, 2008, Invited oral presentation
[Domestic Conference] - An IL-17-Triggered Positive Feedback Loop of IL-6 Signaling in Autoimmune Diseases.
Masaaki Murakami
Annual Meeting of the Japanese Society for Immunology, 2008, English, Invited oral presentation
[Invited], [International presentation] - Hepatic IL-7 controls T cell responses.
Masaaki Murakami
WPI-IFReC Third Seminar, 2008, English, Invited oral presentation
[Invited], [International presentation] - サイトカイン発現ネットワークと自己免疫疾患
村上 正晃
第27回フロンティアバイオサイエンスコロキュウム, 2007, Invited oral presentation
[Invited], [Domestic Conference] - 非免疫系細胞を起点とするサイトカインカスケードの異常と自己免疫疾患
村上 正晃
かずさDNA研究所セミナー, 2007, Invited oral presentation
[Invited], [Domestic Conference] - 網羅的に分子の挙動を捉える技術−cDNAや抗体というリソースを活用した新しい方法
村上 正晃
BMB2007（第30回日本分子生物学会年会・第80回日本生化学会大会 合同大会）, 2007, Invited oral presentation
[Invited], [Domestic Conference] - IL-17 derived from homeostatic proliferating memory/activated CD4+ T cells develops arthritis in F759 mice
Masaaki Murakami
Annual Meeting of the Japanese Society for Immunology, 2007, English, Invited oral presentation
[Invited], [International presentation] - 免疫応答における亜鉛の役割：亜鉛は新しいセカンドメッセンジャーである
村上 正晃
メタロチオンネインおよびメタルバイオサイエンス研究会, 2007, Invited oral presentation
[Invited], [Domestic Conference] - Zinc signaling in dendritic cells
Masaaki Murakami
The 20th Naito Conference on Innate Immunity in Medicine and Biology, 2007, English, Invited oral presentation
[Invited] - 免疫分野における高速セルソーターの応用
村上 正晃
第37回日本免疫学会学術集会, 2007, Invited oral presentation
[Invited], [Domestic Conference] - 免疫分野における高速セルソーターの応用例
村上 正晃
第36回日本免疫学会学術集会, 2006, Invited oral presentation
[Invited], [Domestic Conference] - Non-hematopoietic cell populations play a role for IL-6-mediated enhancement of CD4+ T cell activation
Masaaki Murakami
Annual Meeting of the Japanese Society for Immunology, 2006, English, Invited oral presentation
[Invited], [International presentation] - サイトカイン信号によるCD4+ T細胞の恒常性維持の破綻と免疫異常
村上 正晃
第28回北海道大学獣医学学術交流基金群講演会, 2006, Invited oral presentation
[Invited], [Domestic Conference] - IL-2ファミリーサイトカインによるメモリーCD8+ T細胞の維持機構の解析
村上 正晃
第14回日本癌病態治療研究会, 2005, Invited oral presentation
[Invited], [Domestic Conference] - Hyperactivation of gp130-Mediated STAT3 signaling induces rheumatoid arthritis like disease.
Masaaki Murakami
第8回上原記念生命科学財団, 2005, English, Invited oral presentation
[Invited], [International presentation] - IL-2ファミリーサイトカインによるメモリーCD8+ T細胞の維持機構の解析
村上 正晃
第１３回日本アポトーシス研究会学術集会, 2004, Invited oral presentation
[Invited], [Domestic Conference] - Anti-IL-2-meidated effecter CD8+ T cell activation.
Masaaki Murakami
Annual Meeting of the Japanese Society for Immunology, 2003, English, Invited oral presentation
[Invited], [International presentation] - 生体内でのメモリーT細胞の維持機構
村上 正晃
東京大学医学部免疫学教室セミナー, 2002, Invited oral presentation
[Invited], [Domestic Conference] - The role of CD25+CD4+ T cells in control of memory CD8+ T cells.
Masaaki Murakami
Annual Meeting of the Japanese Society for Immunology, 2002, English, Invited oral presentation
[Invited], [International presentation] - Homeostasis of memory T cells.
Masaaki Murakami
The 2001 AAI Advanced Course in Immunology, 2001, English, Invited oral presentation
[Invited], [International presentation] - The maintenance of memory T cells in vivo.
Masaaki Murakami
Annual Scientific Meeting of the Gerontological Society of America, 2000, English, Invited oral presentation
[Invited], [International presentation]
Affiliated academic society
Research Themes
- 副腎皮質機能亢進症関連肝障害による肝細胞癌発症機序の解明
科学研究費助成事業
01 Apr. 2023 - 31 Mar. 2026
滝口 満喜, 村上 正晃, 佐々木 東, 新坊 弦也, 横山 望
日本学術振興会, 基盤研究(B), 北海道大学, 23K27067 - 副腎皮質機能亢進症関連肝障害による肝細胞癌発症機序の解明
科学研究費助成事業
01 Apr. 2023 - 31 Mar. 2026
滝口 満喜, 村上 正晃, 佐々木 東, 新坊 弦也, 横山 望
日本学術振興会, 基盤研究(B), 北海道大学, 23H02374 - Deep phenotyping toward the precision medicine for chronic airway diseases
Grants-in-Aid for Scientific Research
01 Apr. 2023 - 31 Mar. 2026
今野 哲, 村上 正晃, 鈴木 雅, 杉森 博行, 清水 薫子, 木村 孔一
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hokkaido University, 23H02915 - 迷走神経刺激によるぶどう膜炎抑制治療
科学研究費助成事業
01 Apr. 2022 - 31 Mar. 2025
南場 研一, 村上 正晃, 北市 伸義
日本学術振興会, 基盤研究(C), 北海道大学, 22K09759 - Ocular gateway reflex, which is mediated by sensory nerve, and relapsing control by neurotransmitter
Grants-in-Aid for Scientific Research
01 Apr. 2021 - 31 Mar. 2024
柳井 亮二, 村上 正晃, 園田 康平, 湧田 真紀子, 木村 和博, 寺西 慎一郎
難治性ぶどう膜炎は炎症再燃を繰り返すことにより視機能を喪失させる。ステロイドは炎症再燃を抑制できず、先行研究はケモカインや免疫細胞による急性炎症を対象に病態解明に取り組んでいるが、炎症再燃に関しては決め手がない。私たちは免疫細胞を制限し眼内炎症を抑制する血液眼関門が炎症により妨げられていることに着目して研究をすすめてきた。本研究は、知覚神経による血液眼関門の制御，特に神経伝達物質サブスタンスP による免疫細胞ゲートの形成・制御を精査するとともに、私たちが見出したサブスタンP 由来のFGLM-NH2ペプチドを投与し，より効果的に炎症再燃を抑制することを目的とする。中枢神経系で明らかになった免疫細胞ゲートによる炎症回路：ゲートウェイ反射の観点から眼局所におけるゲートウェイ反射機構を解明し、炎症再燃の本質的理解と解決を目指す画期的な研究である。本研究の目的は、神経伝達物質により部位特異的な免疫病態が誘導され、眼内の炎症再燃が調節されていることをin vivo 系を用いた臨床的な観点から検証する。本年度は、神経伝達物質サブスタンスP による免疫細胞ゲートの形成と局在への影響を検討するため、三叉神経切除によるサブスタンスP 欠乏動物モデルおよび網膜光凝固によるサブスタンスP 過剰発現動物モデルを作成し，各々に自己免疫性ぶどう膜炎を誘導して、各々の群における眼内炎症の評価を行う。免疫細胞ゲート形成の評価は回収した眼球から組織切片を作成し、HE および免疫染色（CD4＋, CD8＋, CD11c+）により自己反応性CD4+T 細胞や抗原提示細胞、マクロファージの細胞数をカウントすることで免疫細胞ゲート形成へのサブスタンスP の影響を確認する。
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Yamaguchi University, 21K09743 - The effect of steroid for calcineurin inhibitors nephrotoxicity in kidney transplant recipients
Grants-in-Aid for Scientific Research
01 Apr. 2021 - 31 Mar. 2024
田邉 起, 村上 正晃, 篠原 信雄, 堀田 記世彦
腎移植後の長期成績の向上にはカルシニューリン阻害薬（CNI）による慢性腎毒性の克服が必要である。これまでのCNI腎毒性の概念は腎細動脈の中膜平滑筋の硝子様変化による血管毒性とされており、これにより腎の間質線維化や尿細管委縮が始まり移植腎機能低下を起こすと考えられていた。この動脈硝子化に代表される血管内皮細胞変化が慢性腎毒性のマーカーとされてきたが、尿細管や間質の上皮細胞系に注目したマーカーが必要である。
近年CNIによる炎症性サイトカインの産生の誘導が指摘されており、慢性炎症のメカニズムのひとつであるNF-κB経路とSTAT3経路の活性化が相乗的に起こる炎症増幅回路の活性化が関与している可能性がある。一方で、免疫抑制剤の一つであるステロイドには抗炎症作用があり、CNIよる炎症性サイトカイン産生誘導を抑制している可能性がある。よって本研究の目的は尿細管間質においてCNI腎毒性をステロイドが軽減しているかを検索し、さらに新規バイオマーカーの開発に取り組むことである。
まずステロイドがCNIによる腎毒性に良い影響を及ぼすかを臨床データおよび経時的な移植腎組織より解析した。当院の腎移植患者でステロイドが継続されている群と、ステロイドを早期に中止した群で、移植腎サンプルの見直しを行った。Periodic acid-Schiff stain（PAS）染色を用いて、これらの細動脈の硝子化を国際基準であるBanff分類のAlternate quantitative scoring for Hyaline Arteriolar Thickening（aahスコア）で3段階に分けて評価した。現段階でステロイド中止群においてCNI毒性が有意に高い結果がでている。この結果はステロイドが慢性腎毒性を抑制する可能性を示す重要な知見である。
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 21K09414 - Development of immunomonitoring system that predicts chronic antibody-mediated rejection in kidney transplant recipients
Grants-in-Aid for Scientific Research
01 Apr. 2021 - 31 Mar. 2024
堀田 記世彦, 村上 正晃, 田邉 起, 篠原 信雄
腎移植の短期成績は飛躍的に向上しているが、長期的にはドナー特異的抗体による慢性抗体関連型拒絶反応(CAAMR)により移植腎機能廃絶となる症例が多く、この克服が長期成績の向上に必要不可欠である。しかし、CAAMRに対する有効な治療法は未だ確立していない。当研究の目的は、CAAMRとなりうる患者を早期に発見する診断法を開発することである。当研究は３つからなり令和3年度の研究実績は以下の通りである。
1. パラフィン移植腎生検標本を用いたCAAMR関連遺伝子の検索：腎機能が正常である患者において移植後1年目、2年目に行ったプロトコール移植腎生検を用いて遺伝子解析した。結果炎症に関連する数種類の遺伝子の発現を組み合わせることにより5年目にCAAMRに至る症例と至らない症例との区別がつく可能性を見いだせた。
２．CAAMR早期診断のための尿中バイオマーカーの検索：過去に報告した尿中ORM1とSYT17の他に数種類の遺伝子候補について解析中である。
３．末梢血リンパ球反応による早期診断法の開発： 200症例につきCFSE/MLR assayを行った結果、腎機能が正常で病理学的にも問題ない患者においてはドナーに対するCD8陽性T細胞の反応は認めないが、CAAMRの患者ではドナーに対するCD8陽性T細胞の強い反応が認めた。また、CD4に関しても同様の所見を認めたが、その中でもTh1，Th17細胞の反応が強く見られた。また、抗ドナー抗体が陽性で腎生検で拒絶を認めない、前CAMR状態の患者においてもCAMRの患者と同様の反応を認めた。CFSE/MLR assayによりCAAMRが未然に診断できる可能性を見いだせた。
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 21K09389 - 破骨細胞に発現する免疫チェックポイント分子シグレック-15の機能と治療応用
科学研究費助成事業
01 Apr. 2021 - 31 Mar. 2024
高畑 雅彦, 村上 正晃, 津田 真寿美
初年度は主に破骨細胞膜上のシグレック-15によるT細胞活性抑制効果の検証を中心におこなった。野生型マウス由来骨髄マクロファージから分化させたシグレック１５を高発現する破骨細胞またはシグレック-15遺伝子欠損マウス由来骨髄マクロファージからII型コラーゲンコートディッシュ上で培養したシグレック１５発現のない破骨細胞を用いてT-cellとの相互作用実験を行った。マウスシグレック-15発現破骨細胞または非発現破骨細胞と細胞透過性色素CFDA-SEで蛍光染色したCD4+T (Th1, Th17)、CD8+T細胞を共培養したところ、T細胞の細胞増殖性には明らかな差は生じなかったものの、シグレック-15発現破骨細胞はT-cellからのサイトカイン（IFNγ, IL-17, IL-22）分泌量を減少させることがわかった。
ヒト末梢血単球由来破骨細胞共培養系とヒトT-cellについても同様の実験を行い、破骨細胞由来のシグレック15はT細胞増殖性には明らかな変化を与えないが、T-cellからのサイトカイン分泌量を減少させ活性を抑制することを確認した。ヒト由来破骨細胞ではシグレック15遺伝子をノックダウンした細胞（単核破骨細胞）を用いた。
２年目の目標であるin vivoでの検証の準備として、転移性骨がんのモデルはマウス乳癌細胞株E0771およびルイス肺がん由来細胞株を免疫不全マウス、野生型マウスおよびシグレック１５遺伝子欠損マウスに尾動脈経由で移植するモデルを作成中であり、免疫不全マウス以外ではモデルの最適化を行なっているところである。また、野生型マウスとシグレック１５遺伝子欠損マウスを用いて、アジュバント誘導関節炎をモデルを作成中である。
日本学術振興会, 基盤研究(B), 北海道大学, 21H03048 - Multi-scale Imaging of Water Molecules using MRI and Isotope Microscope
Grants-in-Aid for Scientific Research
01 Apr. 2021 - 31 Mar. 2024
工藤 與亮, 村上 正晃, 小畠 隆行, 小牧 裕司, 杉森 博行, 坂本 直哉, 亀田 浩之, 安井 正人
①MRI撮像法開発：O-17標識水の存在によるT2値の短縮を定量的に計測してO-17濃度を定量解析するため、プリパルスを利用した高速T2 mapping法を開発して最適化を行った。異なる濃度のO-17標識水を含有した濃度ファントムを作成し、高速T2 mapping法と従来のFSE法によるT2 mapping法の精度を比較した。従来法と比較して高精度のT2値測定が可能となった。
②正常動物・疾患モデル動物でのMRI撮像：正常マウスやラットにてO-17標識水の静脈内投与法や髄腔内投与法、頸動脈内投与法、腹腔内投与法などを確立した。静脈内投与や頸動脈内投与によって脳内の有意なMRI信号変化を確認した。水中毒モデルラットにO-17標識水を腹腔内投与してMRI撮像を行い、AQP4欠損ラットとの比較を行った。AQP4欠損によって脳内の水貯留が増加することが明らかになった。ALSモデルマウス・ラットにてO-17標識水を静脈内投与してMRI撮像を行った。野生型と比較して錐体路での水漏出が増加していることが明らかとなった。
③同位体顕微鏡による水分子イメージング：新たに導入した多機能コーティング装置を用いて凍結下での標本作成から同位体顕微鏡によるイメージングまでの解析手順を確立した。ラット脳にO-18標識水を直接注入し、注入部位でのO-18濃度の上昇を確認した。摘出したラット肝の門脈内にO-18標識水を注入し、血管内や類洞内のO-18濃度の上昇を確認した。
④ヒトでのMRI撮像：認知症患者を対象にしたO-17標識水の髄腔内投与研究にて、特発性正常圧水頭症患者とアルツハイマー型認知症患者で、髄腔内の水吸収速度に差があることを見出した。
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hokkaido University, 21H02857 - ストレスゲートウェイ反射により「病は気から」の分子機構を解き明かす
科学研究費助成事業
01 Apr. 2020 - 31 Mar. 2024
村上 正晃, 田中 勇希, 山崎 理絵
ストレスゲートウェイ(SG)反射では、それ自体では病気を起こさない軽度のストレスが特定の神経回路を活性化し、脳特定血管の変容から当該血管周囲へ自己 反応性T細胞の浸潤を誘導する。その後、さらにその部位の血管周囲に分布する神経回路がATP依存性に活性化し、消化管障害、心機能不全などから突然死が起こる。
R3年度は複数の関節リウマチモデルを用いることで、炎症性疾患で遠隔部位に左右対称な炎症病変を生じさせる分子機構の解明に関して大きな進捗があった。
関節リウマチ、間質性肺炎、乾癬などの炎症性疾患では、遠隔部位に左右対称な炎症病変が形成され、神経系の関連が示唆されていましたが、その実態は長らく全く不明でした。村上らは、新規のゲートウェイ反射が形成に関与していると考え、関節リウマチモデルマウスを用いて検証し、新規の分子機構である「遠隔炎症ゲートウェイ反射」を発見しました。
遠隔炎症ゲートウェイ反射では、関節リウマチモデルマウスの片側の足関節の炎症で生じるATPにより、まず感覚神経、続いて脊髄のプロエンケファリン陽性介在神経の順で活性化し、その後、それに伴って反対側の足関節に分布する感覚神経が活性化しました。その結果、活性化した感覚神経から逆行性にATPが放出され、反対側の血管内皮細胞、線維芽細胞などでIL-6アンプが活性化されることで炎症が誘導されました。すなわち、遠隔炎症ゲートウェイ反射では、ATPが神経伝達物質かつ炎症増悪因子として作用することがわかりました。これらの結果から、遠隔炎症ゲートウェイ反射の神経回路とATPは、関節リウマチ、間質性肺炎、乾癬など遠隔炎症を引き起こす炎症性疾患の治療標的となることが期待されます。
日本学術振興会, 基盤研究(A), 北海道大学, 20H00502 - 精神心理状態の変容による病態修飾の分子機序の解明
科学研究費助成事業
09 Jul. 2021 - 31 Mar. 2023
村上 正晃
精神、心理状態の変化が身体に影響を及ぼすことは経験的にも知られているが、その分子機構は解明されておらず、それを客観的に評価できる バイオマーカーは存在しない。さらに、好ましくない環境や逆に楽しい環境などさまざまな心理状態が脳内でどのような神経回路を形成し健康や病気に影響するのかもほとんど理解されていない。これらの解明は現象が複雑であるがゆえ非常に挑戦的な研究課題であるが、精神、心理状態の変容と病気の関係を捉えられるためにゲートウェイ反射という申請者の独自の発見である観点に絞ってアプローチする。
R3年度は、すでにストレスゲートウェイ反射発見時に実施したものを基本に、テレメトリー、エコーを含む生理学的検証、行動試験を含む神経生理学的検証にて表現型を解析、病理学的検証を実施、さらに、分子生物学的手法のほか、透明化技術、マススペクトロメトリー技術、神経科学技術も採用し進めている。具体的には、透明化法・連続切片と免疫染色法等の組み合わせ、全身連続切片とイメージングMSの組み合わせ、ソート、レーザーマイクロダイセクション法、リボゾームトラップ後の一細胞解析を含むRNAseq、LCMS、ChIPseqなどのRNA発現、分子、DNA修飾の網羅的検討、さらに、オプトジェネティクス、ケモジェネティクスによる特定神経回路機能の検証を実施してストレスゲートウェイ反射の詳細を分子レベルでの解明を遂行中である。
また得られた知見を元に、北大病理学教室、法医学教室と共同研究にて特に加齢突然死、自己免疫疾患などのヒト検体での検証を同時に行なっている。
日本学術振興会, 挑戦的研究(萌芽), 北海道大学, 21K19364 - 副腎－肝臓連関によるイヌ肝細胞癌発症メカニズムの解明
科学研究費助成事業
01 Apr. 2020 - 31 Mar. 2023
滝口 満喜, 村上 正晃, 山崎 淳平, 池中 良徳
犬の肝細胞癌における、ステロイドホルモン産生過剰を起点とする発がん仮説の検証を目指し、前年度に引き続いた検討を行った。2年目となる本年度は肝細胞癌・副腎皮質機能亢進症罹患犬における血中ステロイドホルモン・代謝産物のプロファイリング、ならびに肝臓組織でのエピゲノム変異の解析を遂行した。
ステロイドプロファイリングでは前年度に確立した測定系を発展拡大させ、新たに6種の副腎皮質ホルモンと4種の代謝産物を合わせた、合計19種類のステロイドプロファイル解析が可能となった。この新たな測定系を用いて、肝細胞癌36症例、副腎皮質機能亢進症15症例、併発11症例、コントロール19症例を対象として、血液中のステロイドプロファイルを解析した。しかし、血液中のステロイドプロファイルに疾患特異性、もしくは疾患群間での差が認められなかった。
DNAメチル化の解析では、実験的ステロイドホルモン誘発性脂肪肝、副腎皮質腫機能亢進症併発肝細胞癌および肝細胞癌単独症例の腫瘍組織と腫瘍近傍組織の、合計3種類の肝臓組織を用い、多段階発癌仮説の検証を試みた。その結果、脂肪肝・近傍組織・腫瘍組織と段階的なメチル化変化が存在し、腫瘍においてメチル化レベルの高い遺伝子が6、低い遺伝子が12、抽出できた。
現時点では血中ステロイドプロファイルに肝細胞癌と副腎皮質機能亢進症との関連を示唆する血中ステロイドプロファイリングは見つかっていない。一方で、ステロイド肝から腫瘍への段階的なDNAメチル化レベルの変化が存在することが明らかになった。犬の肝細胞癌においてステロイドが発症に役割を果たしていることは十分に予想され、本年度の成果を複合的かつ詳細に解析することで、多段階発がん説の検証が進む。
日本学術振興会, 基盤研究(B), 北海道大学, 20H03139 - Analysis of epidermal growth factor receptor dependent inflammation amplifier activation in uveitis
Grants-in-Aid for Scientific Research
01 Apr. 2019 - 31 Mar. 2023
南場 研一, 村上 正晃, 北市 伸義
初年度には、ぶどう膜炎群（サルコイドーシス、フォークト-小柳-原田病、ベーチェット病、HLA―B２７関連急性前部ぶどう膜炎）およびコントロール群として健常人について、血清中の上皮増殖因子受容体およびそのリガンドであるエピレグリン等の濃度をマルチプレックス法にて測定し、ぶどう膜炎群ではエピレグリンならびにその他の上皮増殖因子（EGF）受容体のリガンド（アンフィレグリン、ベタセルリン、TGF-アルファ、HB-EGF）がコントロール群と比べ有意に上昇していることを報告した（マンホイットニーのU検定：P＜０.０５）。これらの結果から、他疾患で報告されているようにぶどう膜炎患者においても上皮増殖因子の炎症増幅への関与が示唆された。昨年度はF759遺伝子変異マウスにおいて実験的自己免疫性ぶどう膜網膜炎（ EAU ）が増強されるかどうかを検討する予定であった。F759 遺伝子変異マウスではネガティブシグナルが阻害されてIL-6 産生が亢進し、上皮増殖因子が関与する炎症増幅経路はさらに増強されるため、EAUが強く惹起される可能性が示唆された。F759遺伝子変異マウスを当方の北海道大学医歯学共同研究動物施設に受入する手続きを進めているところで新型コロナウイルス感染拡大のため研究停止となり、現在まで受入が進んでいない。そこで、研究室に凍結保管していたぶどう膜炎患者血清を用いてEGF受容体およびそのリガンドについて測定し、症例数を増やし結果を得た。本年度は、マウスEAUの網脈絡膜を摘出し、網脈絡膜組織のmRNAからcDNAを作成し、マイクロアレイ法にて関連する分子の発現の評価を行った。EGF受容体のリガンドであるエピレグリン、アンフィレグリン、EGFが上昇していること、逆にEGF受容体は発現が低下していることが示され、マウスEAUにおいてEGF受容体を介するシグナル伝達が病態形成に関わっていることが示唆された。
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 19K09985 - Analysis of molecules activating the inflammation amplification loop in fibromatosis of the palmar fascia
Grants-in-Aid for Scientific Research
01 Apr. 2019 - 31 Mar. 2022
Matsui Yuichiro
Dupuytren's contracture is a pathological fibrosis of the palmar aponeurosis that causes irreversible flexion contracture of the fingers and pain in the palmar region. Although several risk factors are known, the detailed pathogenesis of the disease remains unclear. This study focused on the presence of chronic inflammation in Dupuytren's contracture and the previously reported disease-associated genes. The results revealed that the IL-6 amplifier, a mechanism for amplification of chronic inflammation by simultaneous activation of IL-6 and NF-κB in non-immune cells, is activated in this disease. Furthermore, SFRP4, one of the disease-associated genes, was found to contribute to the activation of IL-6 amplifiers.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 19K09639 - Establishment of stress immunology
Grants-in-Aid for Scientific Research
28 Jun. 2019 - 31 Mar. 2021
MURAKAMI Masaaki
We have previously discovered the “stress gateway reflex,” a neuro-immune interaction that lead to fatal gastrointestinal and heart failure by induction of brain micro-inflammation triggered by chronic stress. To find other stress related inflammatory disorders, we firstly focused on light stimulation. Exposure to photopic light down-regulated the ocular inflammation by suppressing beaching of the blood-retina barrier. This discovery also indicates that gateway reflex can be suppressed by environmental stimuli. Moreover, we focused on chronic kidney allograft rejection, a kind of stress associated disease. Pathological analysis revealed that patients’ tubular cells expressed STY17 and ORM1 as well as inflammatory transcription factors. Since these molecules were highly detected in urine, these molecules can be non-invasive candidate biomarkers for stress-mediated inflammatory diseases and will contribute to establish stress immunology in the future.
Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Research (Exploratory), Hokkaido University, 19K22522 - Development of an immunological monitoring system to predict chronic rejection in kidney transplant recipients.
Grants-in-Aid for Scientific Research
01 Apr. 2018 - 31 Mar. 2021
Hotta Kiyohiko
Chronic active antibody-mediated rejection (CAAMR) is the main cause of graft loss in the long-term. Pathological changes during CAAMR occur gradually even without clinical manifestations, followed by dysregulation of the function of the kidney transplant. Therefore, a reliable immunoresponse monitoring system to identify recipients who will develop CAAMR in the future is required.
A mixed lymphocyte reaction (MLR) assay is a method to measure T cells alloreactivity via direct pathway (DP). Recent studies indicate that DP also contribute the pathogenesis of chronic injury. However, there are no reports of MLR assay to monitor CAAMR. Therefore, we tried to develop a novel MLR monitoring system that predicts CAAMR in kidney transplant recipients. To this end, we measured the anti-donor response using our novel MLR in 150 kidney recipients whose graft status were evaluated by graft biopsy and analyzed the relationship between the anti-donor response and pathological findings of allograft.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 18K09156 - 心理免疫学の創成：精神・心理に関連するゲートウェイ反射の同定と解析
科学研究費助成事業
01 Apr. 2018 - 31 Mar. 2021
村上 正晃
日本学術振興会, 基盤研究(A), 北海道大学, 18H04024 - Creation of Space Immunology by space and ground experiments
Grants-in-Aid for Scientific Research
30 Jun. 2017 - 31 Mar. 2019
Murakami Masaaki, Kamimura Daisuke, Arima Yasunobu, Shirakawa Masaki, Shiba Dai, Yumoto Akane, Ueda Hiroki, Tainaka Kazuki
We have reported that gravity stimulation induces regional neural activations to create an immune cell gateway to the CNS via alteration of specific vessels, a phenomenon called the gateway reflex. In this study, we aimed to study a relation between gravity and inflammatory diseases by a combination of ground and space experiments, and develop a research field of the space immunology. We have performed feasibility studies including the establishment of pathogenic T cell clones, overcome of time lag till sampling, and effects of over-gravity and impact during launch, with successful results. Although the space experiment was originally scheduled within the research term, it was postponed, which will be conducted in 2019.
Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Research (Exploratory), Hokkaido University, 17K19537 - Analysis on the mechanism of fibrosis of the palmar fascia in Dupuytren's contracture
Grants-in-Aid for Scientific Research
01 Apr. 2016 - 31 Mar. 2019
Matsui Yuichiro
Activation of STAT3 and NF-κB p65 was identified in the affected palmar fascial tissues from the patients with Dupuytren’s contracture. In addition, in the SNP analysis, genetic loci of risk were observed with uneven distribution in the patients with Dupuytren’s contracture. These included a SNP present between the genes SFRP4 and EPDR1. The activation of STAT3 and NF-κBp65 in the palmar fascial tissues from the patients with Dupuytren’s contracture suggests that an inflammatory circuit is activated in this disease. The relationship between the genes and SNPs with uneven distribution and the inflammatory circuit will be functionally analyzed in a knock-down experiment.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 16K10806 - The mechanisms of chronic inflammation by Gateway Reflex and inflammation amplifier
Grants-in-Aid for Scientific Research
01 Apr. 2015 - 31 Mar. 2018
Murakami Masaaki
A correlation between pain intensity and the pathogenesis of inflammation is poorly established and still unclear. In this application, we elucidated that a pain evoked relapse of multiple sclerosis. Moreover, we revealed that brain micro-inflammation around specific vessels caused by chronic-stress could be switch to activate new neural pathway to regulate organ homeostasis. In addition, we identified positive-regulator of inflammation amplifier by genome wide screening. Among them, we focused on BCR and Rbm10, and clarified the mechanisms of inflammation amplifier.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hokkaido University, 15H04741 - Why does sleep disorder cause diseases?
Grants-in-Aid for Scientific Research
01 Apr. 2015 - 31 Mar. 2017
Murakami Masaaki
The central nervous system (CNS) equips the blood-brain barrier (BBB) to limit exchanges of substances. However, immune-cell infiltration occurs in CNS. We have identified the dorsal vessels of the fifth lumbar (L5) spinal cord as a gateway for immune cells to CNS, which is critical for neuro-inflammation development. In this proposal, how stress-mediated neural activations affect the gateway was examined. I found that specific nerve activations by sleep disorder completely change the gateway site from L5 to the brain, followed by sudden death by gastrointestinal bleeding. This “stress-gateway reflex” explains a classical proverb “Illness starts in the mind.”, which we generally experience but the mechanisms are not well known. By continuing the gateway reflex research, it can be expected that manipulations of local neural activations will be a new therapeutic approach for certain diseases.
Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Exploratory Research, Hokkaido University, 15K15147 - 炎症の増幅回路の交感神経による活性化機構の解析と病態形成への関与
科学研究費助成事業
25 Apr. 2014 - 31 Mar. 2017
村上 正晃, STOFKOVA ANDREA, STOFKOVA Andrea
我々は、線維芽細胞や血管内皮細胞などの非免疫細胞に存在するケモカイン・IL-6の過剰産生機構である「炎症回路」を発見して解析を続け、最近では炎症回路が局所の感覚神経-交感神経の興奮によって過剰に活性化されることを証明した。また、定常状態のマウスでは重力に伴う神経活性化によって、第５腰髄背側血管での炎症回路が過剰に働くことが分かり、さらに、血中に中枢神経系抗原を認識する自己反応生T細胞が存在する場合には、この部位から中枢神経系に侵入して炎症が慢性化し、多発性硬化症に似た病態を形成することが判明した。この局所感覚神経-交感神経の活性化による血管機能変化をゲートウェイ反射と呼んでいる。本研究では、研究が進んでいる多発性硬化症モデル(EAE)に加え、ベーチェット病モデルである実験的自己免疫性ぶどう膜炎（EAU）を新たに利用してこれらの知見をさらに詳細に解析し、自己免疫疾患発症時における神経刺激の役割について明らかにすることを目的とした。EAUでは免疫後10日目からCD4 T細胞を初めとして免疫細胞の網膜への浸潤が認められた。この時期にマウスを暗所から明所へ飼育場所を移動させると、炎症性メディエーターであるインターロイキン6やケモカインの発現や網膜病態の臨床スコアも含め、網膜炎症の状態が変化することを見出した。このことは光の強度が網膜炎症に影響を及ぼすことを示唆しており、光ゲートウェイ反射の存在を示唆している。また、網膜炎症に対する新たな治療法に結びつく可能性が考えられる。これらの結果は学会等で発表し、また論文作製中である。
日本学術振興会, 特別研究員奨励費, 北海道大学, 14F04789 - The novel therapeutic strategy for pulmonary hypertension targeting inflammation amplification loop mediated by IL-6
Grants-in-Aid for Scientific Research
01 Apr. 2013 - 31 Mar. 2015
NAKAOKA YOSHIKAZU, SHIRAI Mikiyasu, MURAKAMI Masaaki, KOMURO Issei
The molecular mechanisms of interleukin-6(IL-6)-mediated pathogenesis of PAH have been elusive. Here, we identified IL-21 as a novel downstream target of IL-6-signaling in PAH. First, we found that IL-6 blockade by the monoclonal anti-IL-6 receptor antibody, MR16-1, ameliorated hypoxia-induced pulmonary hypertension (HPH) and prevented the hypoxia-induced accumulation of Th17 cells and M2 macrophages in the lungs. Consistently, the expression levels of IL-17 and IL-21 genes, one of the signature genes for Th17 cells, were significantly upregulated after hypoxia exposure in the lungs of mice treated with control antibody, but not in those treated with MR16-1. Whereas IL-17 blockade with an anti-IL-17A neutralizing antibody had no effect on HPH, IL-21 receptor-deficient mice were resistant to HPH and exhibited no significant accumulation of M2 macrophages in the lungs. These findings suggest that IL-6/IL-21-signaling is critical in the pathogenesis of pulmonary arterial hypertension.
Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Exploratory Research, Osaka University, 25670386 - Proposal of a disease model by optogenetics
Grants-in-Aid for Scientific Research
01 Apr. 2012 - 31 Mar. 2015
MASAAKI Murakami
We have stimulated nerves in sympathetic ganglia around the fifth lumbar cord by using light stimulation in Thy1 channel rhodopsin transgenic mice. This stimulation induced the increment of chemokine expression in dorsal vessels in the fifth lumbar cord. Furthermore, an intensity of chemokine expression was correlated with intensity and times of light stimulations. And we could induce the development of EAE by using light stimulations for sympathetic ganglia in MOG reactive T cell transferred mice. This result indicated that regional neural activation could induce the development of EAE and put forward a new model to analysis of autoimmune diseases including multiple sclerosis.
Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Exploratory Research, 24659221 - Formation of blood-brain barrier and activation of Interleukin-6 amplifier
Grants-in-Aid for Scientific Research
01 Apr. 2012 - 31 Mar. 2015
MURAKAMI Masaaki
Activation of NFkB and STAT induces massive production of chemokines in non-immune cells, which leads to local inflammation. We have been studying this inflammation amplifying mechanism, termed inflammation amplifier. In this study, we aimed to characterize mechanisms by which immune cells infiltrate into the central nervous system (CNS), and regulation of blood-brain barrier. In a murine model of multiple sclerosis, EAE, we found that high-performance MRI revealed that inflammation with edema occurred at fifth lumbar region where immune cells firstly enter the CNS. In addition, this edema was associated with ischemia/reperfusion injury that deteriorated the CNS inflammation. We also discovered that various stresses modulated the entry sites of immune cells into the CNS and altered the development of EAE in mice.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), 24390098 - Characterization of intracellular Zn signaling and its relationship to diseases
Grants-in-Aid for Scientific Research
01 Apr. 2012 - 31 Mar. 2015
HIRANO Toshio, MURAKAMI Masaaki
Zinc is one of the essential metal elements, which is indispensable for the functions of various molecules in the body. However, it is not well understood how zinc levels inside and/or outside cells are regulated. In the course of research about interleukin-6 and its signal transduction, we found that zinc acts as a second messenger in a cell, and established a scientific field of “zinc signaling”. In this study, we revealed molecular mechanisms and physiological functions of zinc signaling using various knock-out mice related to zinc signaling such as zinc-binding molecules and zinc transporters.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (A), Osaka University, 24249028 - 急性期蛋白による自己免疫疾患・感染症の制御
科学研究費助成事業
2010 - 2011
村上 正晃
本研究はT細胞の生体内での反応性を肝臓などの非免疫臓器からのサイトカイン発現を起点に検討することを目的としている。この目的のために以下の3つの実験を行った。
1. IL-7を肝臓特異的に欠損させたマウスでの自己免疫疾患の発症
IL-7floxマウスを京都大学の生田先生からいただきアルブミンCreマウスとかけ合わせて肝臓特異的にIL-7が欠損した変異マウスを作製した。多発性硬化症モテルの実験的脳脊髄炎(EAE)を誘導したところ有意にその発症か抑制された。この結果は研究代表者が2009年にImmunlty誌に発表したハイドロダイナミック法とshRNAを用いた方法を同様のものであった。すでにIL-7を肝細胞から誘導する1型IFN受容体の欠損でも同様な表現型を得ることができた。
2. 脊髄の血管内皮細胞に存在する病原T細胞の中枢神経系への侵入口
第5腰椎の背側の血管の内皮細胞にサイトカインIL-6と神経刺激によるノルアドレナリンの刺激にてSTAT3とNFkBが活性化してケモカインの過剰発現系IL-6アンプが活性化し免疫細胞の中枢神経系への入り口となっていることが判った。血液中に中枢神経系の抗原に対する自己反応性T細胞が存在すればこの部位から侵入して病気を発症した(Cell 2012)。
3. 血管内皮細胞でのケモカイン発現機構IL-6アンプの制御潰伝子のゲノムワイドな解析
実験2にて解析したIL-6アンプの活性化制御遺伝子を同定する目的でshRNAを搭載したレンチウイルスを用いたゲノムワイドな解析を行った。その結果、IL-6アンプの活性化は1000個以上の遺伝子にて制御されていることが判った。これらの遺伝子にはこれまで遺伝学的に病気、病態との関運か証明されたのもが10%以上存在して疾患関連遺伝子が濃縮されていることが判った(under revlsion)。
日本学術振興会, 特定領域研究, 大阪大学, 22021029 - Controlling of chronic inflammatory diseases via regulation of inflammation stroma cells
Grants-in-Aid for Scientific Research
2009 - 2011
MURAKAMI Masaaki, KAMIMURA Daisuke
We defined the inflammation stroma cells as cells having excessive chenokine production after NFkB and STAT3 stimulation. The inflammation stroma cells have type 1 collagen molecules and include endothelial cells, fibroblasts, astrocytes, and epithelial cells. The main founding in this project is that excessive activation of the he inflammation stroma cells by an excessive neural activation particularly via sympathetic neuron' s creates a gateway for immune cells in blood vessels including autoreactive CD4+ T cells followed by the development of an autoimmune disease.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Osaka University, 21390120 - Activation of Zinc signal and its biological significance
Grants-in-Aid for Scientific Research
2008 - 2010
HIRANO Toshio, MURAKAMI Masaaki, KAMIMURA Daisuke, FUKUSHIMA Toru, FUKADA Toshiyuki
We here attempt to investigate intracellular Zn signaling, which is important for cell fate and/or cell activation status determination followed by various diseases and disorders. We mainly have three results, which are obtained by this grant. (I) Investigation of intracellular Zn signals, (II) Molecular basis of Zn signal to analyze Zn-binding sites in the target molecules and their mechanism, and (III) in vivo significances of Zn signal using various Zn-related molecule deficient mice and several disease/disorder models.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (A), Osaka University, 20249030 - 肝臓からのサイトカインの発現とT細胞反応性の制御
科学研究費助成事業
2008 - 2009
村上 正晃
私たちは、線維芽細胞にてIL-6信号によって生体内のIL-7の発現量が制御されていることを示すことができた。最近、"LPSが肝細胞からIL-7を免疫細胞由来のTRIF=>IFNβを介して誘導してT細胞の反応性を亢進させる"ことを発見し、論文に発表した(Immunity 2009)。今年度は以下の2つの点に関して実験を行った。
(i) LPSあるいは他のTLRリガンドの刺激にて肝臓から発現されてT細胞の反応性に大きな影響を与えるIL-7以外の分子を同定することを目的にDNAアレーから自己免疫誘導時に肝臓にて発現する可溶性分子を同定した。これまでに約20個の分子を肝臓にて強制発現させてT細胞の分裂能を指標に解析した。その結果、2つの分子を強制発現させた場合にT細胞の分裂が促進した。現在、それらの分子に関して肝臓特異的にノックダウンさせたときのT細胞依存性自己免疫疾患の発症を解析している。
(ii) マウス生体へのTLRリガンド刺激にて肝臓からのIL-7発現は上昇したが、脾臓およびリンパ節からのIL-7の発現は減少した。脾臓あるいはリンパ節では線維芽細胞が主にIL-7を産生している事が知られている。肝臓と線維芽細胞でのIL-7発現制御メカニズムを比較解析して『なぜ、脾臓およびリンパ節にてTLRリガンド刺激後にIL-7の発現が低下する必要が有るのか?』を解析している。各種ノックアウトマウスをLPS刺激してリンパ節からのIL-7発現を解析した。現在までに25種類のノックアウトマウスにて解析を行ったが、その発現がLPS刺激前後に変化しない変異マウスは同定できていない。そのため、現在、SOCS3を線維芽細胞特異的にノックアウトしたマウスを作製してIL-7発現を解析している。
日本学術振興会, 特定領域研究, 大阪大学, 20060015 - Regulation of Immune responses and autoimmune diseases by cytokines
Grants-in-Aid for Scientific Research
2003 - 2007
HIRANO Toshio, MURAKAMI Masaaki, YAMASHITA Susumu
Our aim of this study was to know how Y759F mutation in gp130, an IL-6 signal transducer, induces an autoimmune arthritis disease in vivo and to investigate a role of IL-6-mediated signaling in the normal immune responses. We obtained two important concepts showing how tissue specific autoimmune diseases are induced as described below.
(1) Excess IL-7 expression induced by activation of non-hematopoietic cells via an excess IL-6 signaling triggers an excess homeostatic proliferation of CD4+ T cells followed by the development of autoimmune arthritis in F759 mice. We demonstrated how a dysregulated interaction between non-hematopoietic cells and hematopoietic cells, CD4+ T cells, induces a tissue specific autoimmune diseases in vivo.
(2) There is an IL-17-mediated IL-6 positive feedback loop in non-hematopoietic cells even in normal condition in vivo. Dysregulation of the IL-6 loop by a genetic abnormality such as Y759F mutation in F759 mice induces an excess production of IL-6 via the loop followed by the development of autoimmune arthritis.
Moreover, we proved the existence of intracellular Zinc signaling, which is also important for regulation of immune cell functions.
Japan Society for the Promotion of Science, Grant-in-Aid for Specially Promoted Research, Osaka University, 15002008 - Acquisition of Signal Information for Immune Surveillance and Determination of Immune Responses
Grants-in-Aid for Scientific Research
2003 - 2006
SAITO Takashi
We aimed to clarify the mechanism on the acquisition of the information of immune recognition and regulation of immune responses. As the central mechanism of immune surveillance, dendritic cells (DC) first recognize pathogens upon infection, and then innate immunity is activated, which in turn induces antigen-specific recognition and activation of T cells. In this project, we have clarified that IRAK-4, a central regulatory serin/threonine kinase in innate immune signaling, plays also a critical role in T cell activation as the central response in the adaptive immunity. In IRAK-4-deficient mice, proliferation and cytotoxic function of CD8+ T cells were impaired upon LCMV infection. We analyzed whether the impaired response was attributed to the defects in innate response by DCs or T cells by using T cell transfer experiments, and found that T cell activation was impaired in both MHC class I and II-restricted responses. Indeed, we found that not only in vivo T cell responses but also in vitro responses including allogenic responses, super-antigen responses, and responses upon anti-TCR stimulation. By analyzing the defective signaling pathways, particularly NF-AT or NF-κB activation pathways, we found that NF-κB activation was suppressed and impaired phosphorylation of PKCθ appeared to be responsible for the defective NF-κB activation. These results indicate that IRAK-4 plays a critical role in TCR activation signals by directing towards NF-κB activation. We further analyzed the mechanism of IRAK-4-mediated NF-κB specific activation, and found that IRAK-4 associates with ZAP-70 in the over-expression system. IRAK-4 appears to be recruited together with ZAP-70 to the vicinity of TCR upon stimulation, and is involved in activation regulation. Our result that IRAK-4 is important for NF-KB activation in both innate and acquired immunities suggests that NF-κB activation by IRAK-4 has been conserved through phylogenic development.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research on Priority Areas, 15078201 - Identification of a chromosomal region that is responsible for memory T cell homeostasis in a mutant mouse.
Grants-in-Aid for Scientific Research
2002 - 2003
MURAKAMI Masaaki
It is well known that memory T cells proliferate faster and react to the pathogens stronger compared to naive T cells. I found a female mutant mouse carrying excess amount of memory T cells of both CD4+ and CD8+ in a SPF colony in National Jewish Medical Center, Denver, CO. The phenotype is inherited as an autosomal recessive manor. Thymus size is small (about 10% of controls) and the numbers of double positive cells reduces dramatically. T cell differentiation is partially but dominantly blocked at a step where preTCR signaling is necessary named DN3. Platelets significantly increased in serum and this result is consistent with excess amount of megakaryocytes in spleen. In addition, the number of immature B cells decreased significantly and differentiation of B cells is blocked at large preB stage where preBCR signaling is important. I performed bone marrow transplantation experiment to analyze if the mutation in lymphoid progenitor is or if it in microenvironment is necessary for the phenotype of T and B cells in the mutant mice. The mutation in lymphoid progenitor cells themselves is necessary to see the phenotype. In order to identify a DNA fragment carrying a responsible gene that induces the phenotype in the mutant mice, we employed SSPL method. We crossed B10#4 mice with NZB mice to get F2 mice and got over 100 phenotype + and -offspring. We identified 1cM DNA fragment in chromosome #2 that is responsible for the mutant and the fragment has about 40 genes according to NCBI database. Result of RT-PCR experiment for a gene in the fragment was fascinating, since splicing pattern of the gene is different between the B10#4 and control mice. I analyzed sequence of the gene and found that there were two mutations in the introns of the gene.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Osaka University, 14570275 - 過剰のメモリーT細胞を持ち膵島炎を発症する突然変異マウスからの責任遺伝子単離
科学研究費助成事業
2002 - 2002
村上 正晃
1)申請者はデンバーのマラック教授の教室に留学中に正常C57BL10コロニーから末梢血中に過剰のメモリー表現型T細胞を持ち、肝臓および膵島にリンパ球浸潤が認められる突然変異マウスBL10#4を見つけることができた。その後の研究から、この形質は常染色体劣勢遺伝し、1遺伝子で規定されること、T細胞およびB細胞分化の両方に異常が認められ、それぞれプレTおよびプレB細胞受容体信号が必要な時期(プレT細胞から未熟T細胞及びプレB細胞から未熟B細胞)で重度な分化障害が有ること、巨核球数が増加して血小板が正常個体の10倍以上にまで増加していること、中程度の貧血が認められ、抗赤血球抗体の検出できる個体が有ること、骨髄移植の実験から変異表現型は環境因子では無く、骨髄細胞自体に由来することが判明した。ヒトの1型糖尿病を含めた自己免疫疾患は多因子疾患であるが、それらの発症に関連する遺伝的要因の一つに、このマウスの責任遺伝子が成りうる可能性がある(日本免疫学会、東京、2002年、発表)。
2)申請者は特定領域研究、ゲノム医科学に、本研究課題にて本年度から参加させていただきました。本年度、本予算を用いてBL10#4とNZBマウスをかけ合わせて、100匹以上の形質陽性および陰性F2マウスを得ることができた。それらのF2マウスの肝臓からDNAを抽出し、BL10とNZBで長さの異なるMITマーカーを用いてSSLP法にてBL10#4の形質の責任遺伝子の存在を解析した。幸運なことに責任遺伝子の存在する1cM程度の領域を2番染色体に同定することができた。セレラ社のデータベースで解析してみるとその領域には約45個の遺伝子が存在していることが判明した。
日本学術振興会, 特定領域研究, 大阪大学, 14013001 - Analysis of regulation of host defense response by osteopopontin and its applocation to diagnosis and therapy strategy
Grants-in-Aid for Scientific Research
1998 - 2000
UEDE Toshimitsu, MAEDA Masahiro
1. Highly metastatic adenocarcinoma cells tend to secrete osteopontin(OPN). OPN binds to β1 integrin-containing receptors in an autocrine fashion and induce motility of tumor cells. The association of β1 integrins with CD44v on tumor cell surface is essential for OPN-induced tumor cell motility.
2. The new-vessel formation as defined by CD34 positive endothels was significantly increased in OPN and VEGF positive stage I lung adenocarcinoma tissues and corelated very well with poor prognosis of patients.
3. Upon high fat diet feeding, OPN transgenic mice developed considerably severe atherosclerosis as compared to control mice. In OPN transgenic mice, macrophages within atherosclerotic lesions expressed significant levels of OPN.
4. Upon intravenous injection of zymosan, mice develoved liver granuloma, the development of granuloma was significantly inhibited by simultaneous injection of anti-OPN antibody, indicating the critical role of OPN in the granuloma development.
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B)., HOKKAIDO UNIVERSITY, 10557024 - 新しいCTLA4結合分子、ACBMのcDNA単離とその機能解析
科学研究費助成事業
1997 - 1997
村上 正晃, 上出 利光
T細胞の活性化はT細胞受容体からの信号と接着分子からの補助信号が必須である。我々は補助信号分子としてCD28/CTLA4を研究してきた。CD28/CTLA4は共通のリガンドであるB7-1/B7-2を持つ、T細胞上の分子である。CD28は静止期のT細胞から発現していて活性化のための副信号を伝達する。一方、CTLA4は活性化T細胞に発現誘導され、T細胞の不活性化を誘導する。本研究では新たに発見したB細胞上のCTLA4結合分子ACBMの機能解析とcDNAの単離を目的としている。新しいCTLA4結合蛋白を同定するために既知のリガンド、B7-1/B7-2と結合できない可溶性変異型CTLA4の作製を行った。この分子を用いて細胞株を検索し、結合できる細胞が新しいCTLA4結合蛋白を発現していると考えた。CD28/CTLA4の細胞外領域には動物間で高度に保存されたMYPPPYモチーフが存在したのでこのMYPPPYモチーフに点突然変異を加えていった。その結果、最後のPYをAに置換したPYAA変異体がB7-1/B7-2と結合できなかった。このPYAA分子の細胞外領域をIgG1のFc領域と結合させたPYAAIgGを作製し、細胞株を検索してマウス未熟B細胞株、WEHI231細胞に結合を認めた。WEHI231からACBM分子を免疫沈降すると130kDのホモダイマーであることが判明した。ACBMのcDNAを単離するためにCTLA4IgG/PYAAIgGを用いたアフィニティーカラムを作製した。しかし、CTLA4IgG/PYAAIgGの単体への共有結合後、ACBMとの結合が弱まり、目的よりかなり少量のACBMを精製できたのみであった。そのため、精製を続けるためには大量のCTLA4IgG/PYAAIgG分子が必要となり、アデノウイルスを用いた発現系を作製した。この発現系を用いてmgオーダーのCTLA4IgG/PYAAIgGを得ることが可能となり、ACBMの精製とあわせて、CD28/CTLA4-B7/ACBM信号の生体内での機能解析が可能となった。
日本学術振興会, 重点領域研究, 北海道大学, 09271201
