Researcher Database

Masaaki Murakami
Institute for Genetic Medicine Molecular Pathogenesis
Professor

Researcher Profile and Settings

Affiliation

  • Institute for Genetic Medicine Molecular Pathogenesis

Job Title

  • Professor

J-Global ID

Research Interests

  • Endothelial cells   Helper T cells   Neural Singlaing pathway   Chronic Inflammation   Cytokines   ゲーtウェイ反射   IL-6アンプ   

Research Areas

  • Life sciences / Immunology
  • Life sciences / Experimental pathology

Academic & Professional Experience

  • 2014 - Today Institute for Genomic Medicine and Graduate School of Medicine Division of Molecular Neuroimmunology Professor

Education

  • 1989/04 - 1993/03  Osaka University  Graduate School of Medicine
  • 1984/04 - 1989/03  Hokkaido University  School of Veterinary Medicine

Association Memberships

  • 日本免疫学会   日本癌学会   Japanese Society for Moleculur Biology   日本分子生物学会   Japanese Society for Immunology   Japanese Cancer Association   

Research Activities

Published Papers

  • 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 Cell Press 24 (8) 2196 - 2210 2108/08/24 [Refereed][Not invited]
     
    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.
  • 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 0027-8424 2019/08/27 [Refereed][Not invited]
     
    © 2019 National Academy of Sciences. All rights reserved. Although KRAS and TP53 mutations are major drivers of pancreatic ductal adenocarcinoma (PDAC), the incurable nature of this cancer still remains largely elusive. ARF6 and its effector AMAP1 are often overexpressed in different cancers and regulate the intracellular dynamics of integrins and E-cadherin, thus promoting tumor invasion and metastasis when ARF6 is activated. Here we show that the ARF6-AMAP1 pathway is a major target by which KRAS and TP53 cooperatively promote malignancy. KRAS was identified to promote eIF4A-dependent ARF6 mRNA translation, which contains a quadruplex structure at its 5′-untranslated region, by inducing TEAD3 and ETV4 to suppress PDCD4; and also eIF4E-dependent AMAP1 mRNA translation, which contains a 5′- terminal oligopyrimidine-like sequence, via up-regulating mTORC1. TP53 facilitated ARF6 activation by platelet-derived growth factor (PDGF), via its known function to promote the expression of PDGF receptor β (PDGFRβ) and enzymes of the mevalonate pathway (MVP). The ARF6-AMAP1 pathway was moreover essential for PDGF-driven recycling of PD-L1, in which KRAS, TP53, eIF4A/4Edependent translation, mTOR, and MVP were all integral. We moreover demonstrated that the mouse PDAC model KPC cells, bearing KRAS/TP53 mutations, express ARF6 and AMAP1 at high levels and that the ARF6-based pathway is closely associated with immune evasion of KPC cells. Expression of ARF6 pathway components statistically correlated with poor patient outcomes. Thus, the cooperation among eIF4A/4E-dependent mRNA translation and MVP has emerged as a link by which pancreatic driver mutations may promote tumor cell motility, PD-L1 dynamics, and immune evasion, via empowering the ARF6-based pathway and its activation by external ligands.
  • 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 2019/07/25 [Refereed][Not invited]
     
    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.
  • Tanaka H, Arima Y, Kamimura D, Tanaka Y, Takahashi N, Uehata T, Maeda K, Satoh T, Murakami M, Akira S
    J Exp Med. 2019/05 [Refereed][Not invited]
  • Heishima K, Iwasaki R, Kawabe M, Murakami M, Sakai H, Maruo K, Mori T
    Journal of the American Animal Hospital Association 0587-2871 2018/11 [Refereed][Not invited]
  • 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 0022-1767 2018/10 [Refereed][Not invited]
  • 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 0022-1767 2018/10 [Refereed][Not invited]
  • 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 2018/09 [Refereed][Not invited]
  • Itabashi T, Arima Y, Kamimura D, Higuchi K, Bando Y, Takahashi-Iwanaga H, Murakami M, Watanabe M, Iwanaga T, Nio-Kobayashi J
    Neurochemistry international 118 176 - 184 0197-0186 2018/09 [Refereed][Not invited]
  • Fujita M, Yamamoto Y, Jiang JJ, Atsumi T, Tanaka Y, Ohki T, Murao N, Funayama E, Hayashi T, Osawa M, Maeda T, Kamimura D, Murakami M
    The Journal of investigative dermatology 0022-202X 2018/09 [Refereed][Not invited]
  • Kamimura D, Ohki T, Arima Y, Ota M, Murakami M
    Neurochemistry international 0197-0186 2018/09 [Refereed][Not invited]
  • Kazuki Tainaka, Tatsuya C Murakami, 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 2018/08/21 [Refereed][Not invited]
     
    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.
  • Kamimura D, Ohki T, Arima Y, Murakami M
    International immunology 30 (7) 281 - 289 0953-8178 2018/06 [Refereed][Not invited]
  • Kijimoto-Ochiai S, Matsumoto-Mizuno T, Kamimura D, Murakami M, Kobayashi M, Matsuoka I, Ochiai H, Ishida H, Kiso M, Kamimura K, Koda T
    Glycobiology 28 (5) 306 - 317 0959-6658 2018/05 [Refereed][Not invited]
  • R. Iwasaki, M. Murakami, M. Kawabe, K. Heishima, H. Sakai, T. Mori
    Veterinary and Comparative Oncology 16 (1) 140 - 147 1476-5810 2018/03 [Refereed][Not invited]
     
    © 2017 John Wiley & Sons Ltd The accurate evaluation of sternal lymph nodes (StLNs) is critical for the staging of canine thoraco-abdominal tumours. Computed tomography (CT) provides a non-invasive means of assessing StLNs, but its diagnostic accuracy for identifying metastases is unclear. In this retrospective cross-sectional study, we assessed the diagnostic power of various CT measurements. Fifty-seven dogs that underwent concurrent CT and cytological examination of the StLNs were enrolled retrospectively. The size, shape, X-ray attenuation and uniformity of the StLNs were assessed. The dogs were divided into metastasis-negative (n = 21) and metastasis-positive (n = 36) groups. Logistic regression analysis showed that the size (StLN-to-second sternebra ratio [ratio-size]) and precontrast attenuation were significantly different between groups. Combining these parameters achieved a specificity and positive predictive value of 100% (cut-off values: 1.0, 37.5 Hounsfield units, respectively). This suggests that the combination of ratio-size and precontrast attenuation is effective for differentiating metastasis to the StLNs on CT.
  • Takahashi J, Murakami M, Mori T, Iwahashi H
    Scientific reports 8 (1) 2728  2018/02 [Refereed][Not invited]
  • Atsumi T, Suzuki H, Jiang JJ, Okuyama Y, Nakagawa I, Ota M, Tanaka Y, Ohki T, Katsunuma K, Nakajima K, Hasegawa Y, Ohara O, Ogura H, Arima Y, Kamimura D, Murakami M
    International immunology 29 (12) 581 - 591 0953-8178 2017/12 [Refereed][Not invited]
  • 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 2211-1247 2017/11 [Refereed][Not invited]
     
    Foxp3(+) regulatory T (Treg) cells, which suppress immune responses, are highly proliferative in vivo. However, it remains unclear how the active replication of Treg cells is maintained in vivo. Here, we show that branched-chain amino acids (BCAAs), including isoleucine, are required for maintenance of the proliferative state of Treg cells via the amino acid transporter Slc3a2-dependent metabolic reprogramming. Mice fed BCAA-reduced diets showed decreased numbers of Foxp(3+) Treg cells with defective in vivo proliferative capacity. Mice lacking Slc3a2 specifically in Foxp(3+) Treg cells showed impaired in vivo replication and decreased numbers of Treg cells. Slc3a2-deficient Treg cells showed impaired isoleucine-induced activation of the mTORC1 pathway and an altered metabolic state. Slc3a2 mutant mice did not show an isoleucine-induced increase of Treg cells in vivo and exhibited multi-organ inflammation. Taken together, these findings demonstrate that BCAA controls Treg cell maintenance via Slc3a2-dependent metabolic regulation.
  • Yuki Tanaka, Yasunobu Arima, Daisuke Kamimura, Masaaki Murakami
    FRONTIERS IN IMMUNOLOGY 8 1321  1664-3224 2017/10 [Refereed][Not invited]
     
    The gateway reflex is a new phenomenon that explains how immune cells bypass the blood-brain barrier to infiltrate the central nervous system (CNS) and trigger neuroinflammation. To date, four examples of gateway reflexes have been discovered, each described by the stimulus that evokes the reflex. Gravity, electricity, pain, and stress have all been found to create gateways at specific regions of the CNS. The gateway reflex, the most recently discovered of the four, has also been shown to upset the homeostasis of organs in the periphery through its action on the CNS. These reflexes provide novel therapeutic targets for the control of local neuroinflammation and organ function. Each gateway reflex is activated by different neural activations and induces inflmammation at different regions in the CNS. Therefore, it is theoretically possible to manipulate each independently, providing a novel therapeutic strategy to control local neuroinflammation and peripheral organ homeostasis.
  • 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 2050-084X 2017/08 [Refereed][Not invited]
     
    Impact of stress on diseases including gastrointestinal failure is well-known, but molecular mechanism is not understood. Here we show underlying molecular mechanism using EAE mice. Under stress conditions, EAE caused severe gastrointestinal failure with high-mortality. Mechanistically, autoreactive-pathogenic CD4+ T cells accumulated at specific vessels of boundary area of third-ventricle, thalamus, and dentate-gyrus to establish brain micro-inflammation via stress gateway reflex. Importantly, induction of brain micro-inflammation at specific vessels by cytokine injection was sufficient to establish fatal gastrointestinal failure. Resulting micro-inflammation activated new neural pathway including neurons in paraventricular-nucleus, dorsomedial-nucleus-ofhypothalamus, and also vagal neurons to cause fatal gastrointestinal failure. Suppression of the brain micro-inflammation or blockage of these neural pathways inhibited the gastrointestinal failure. These results demonstrate direct link between brain micro-inflammation and fatal gastrointestinal disease via establishment of a new neural pathway under stress. They further suggest that brain micro-inflammation around specific vessels could be switch to activate new neural pathway(s) to regulate organ homeostasis.
  • 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 0022-1007 2017/05 [Refereed][Not invited]
     
    Inappropriate IL-17 responses are implicated in chronic tissue inflammation. IL-23 contributes to Trypanosoma cruzi-specific IL-17 production, but the molecular mechanisms underlying regulation of the IL-23-IL-17 axis during T. cruzi infection are poorly understood. Here, we demonstrate a novel function of BATF2 as a negative regulator of Il23a in innate immune cells. IL-17, but not IFN-gamma, was more highly produced by CD4(+) T cells from spleens and livers of T. cruzi-infected Batf2(-/-) mice than by those of wild-type mice. In this context, Batf2(-/-) mice showed severe multiorgan pathology despite reduced parasite burden. T. cruzi-induced IL-23 production was increased in Batf2(-/-) innate immune cells. The T. cruzi-induced enhanced Th17 response was abrogated in Batf2(-/-) Il23a(-/-) mice. The interaction of BATF2 with c-JUN prevented c-JUN-ATF-2 complex formation, inhibiting Il23a expression. These results demonstrate that IFN-gamma-inducible BATF2 in innate immune cells controls Th17-mediated immunopathology by suppressing IL-23 production during T. cruzi infection.
  • 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 0022-1767 2017/01 [Refereed][Not invited]
  • Nakagawa I, Murakami M
    Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology 40 (3) 160 - 168 0911-4300 2017 [Refereed][Not invited]
  • 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 [Refereed][Not invited]
     
    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.
  • 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 2016/11 [Refereed][Not invited]
  • 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 0022-1767 2016/10 [Refereed][Not invited]
     
    The breakpoint cluster region (BCR) is known as a kinase and cause of leukemia upon fusing to Abl kinase. In this study, we demonstrate that BCR associated with the alpha subunit of casein kinase II (CK2 alpha), rather than BCR itself, is required for inflammation development. We found that BCR knockdown inhibited NF-kappa B activation in vitro and in vivo. Computer simulation, however, suggested that the putative BCR kinase domain has an unstable structure with minimal enzymatic activity. Liquid chromatography-tandem mass spectrometry analysis showed that CK2 alpha associated with BCR. We found the BCR functions are mediated by CK2 alpha. Indeed, CK2 alpha associated with adaptor molecules of TNF-alpha R and phosphorylated BCR at Y177 to establish a p65 binding site after TNF-alpha stimulation. Notably, p65 S529 phosphorylation by CK2 alpha creates a p300 binding site and increased p65-mediated transcription followed by inflammation development in vivo. These results suggest that BCR-mediated inflammation is dependent on CK2 alpha, and the BCR-CK2 alpha complex could be a novel therapeutic target for various inflammatory diseases.
  • 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 0953-8178 2016/03 [Refereed][Not invited]
     
    KDEL receptor 1 (KDELR1) regulates integrated stress responses (ISR) to promote naive T-cell survival in vivo. In a mouse line having nonfunctional KDELR1, T-Red (naive T-cell reduced) mice, polyclonal naive T cells show excessive ISR and eventually undergo apoptosis. However, breeding T-Red mice with TCR-transgenic mice bearing relatively high TCR affinity rescued the T-Red phenotype, implying a link between ISR-induced apoptosis and TCR-mediated signaling. Here, we showed that strong TCR stimulation reduces ISR in naive T cells. In mice lacking functional KDELR1, surviving naive T cells expressed significantly higher levels of CD5, a surrogate marker of TCR self-reactivity. In addition, higher TCR affinity/avidity was confirmed using a tetramer dissociation assay on the surviving naive T cells, suggesting that among the naive T-cell repertoire, those that receive relatively stronger TCR-mediated signals via self-antigens survive enhanced ISR. Consistent with this observation, weak TCR stimulation with altered peptide ligands decreased the survival and proliferation of naive T cells, whereas stimulation with ligands having higher affinity had no such effect. These results suggest a novel role of TCR-mediated signals in the attenuation of ISR in vivo.
  • 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 2016 [Refereed][Not invited]
  • 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  1664-3224 2015/12 [Refereed][Not invited]
     
    The survival of naive T cells is believed to require signals from TCR-pMHC interactions and cytokines such as IL-7. In contrast, signals that negatively impact naive T cell survival are less understood. We conducted a forward genetic screening of mice and found a mutant mouse line with reduced number of naive T cells (T-Red mice). T-Red mice have a point mutation in the Kdelr1 gene, and their naive T cells show enhanced integrated stress response (ISR), which eventually induces their apoptosis. Therefore, naive T cells require a KDEL receptor-mediated mechanism that efficiently relieves cellular stress for their survival in vivo. Interestingly, naive T cells expressing TCR with higher affinity/avidity to self-antigens survive in T-Red mice, suggesting the possible link between TCR-mediated survival and ISR-induced apoptosis. In this article, we discuss the regulation of naive T cell homeostasis, keeping special attention on the ISR and TCR signal.
  • Kaori Nakanishi, Makoto Nishida, Masaya Harada, Tohru Ohama, Noritaka Kawada, Masaaki Murakami, Toshiki Moriyama, Keiko Yamauchi-Takihara
    SCIENTIFIC REPORTS 5 14230  2045-2322 2015/09 [Refereed][Not invited]
     
    While aging is unavoidable, the aging mechanism is still unclear because of its complexity. Smoking causes premature death and is considered as an environmental aging accelerator. In the present study, we focused on the influence of smoking to the serum concentration of anti-aging protein alpha-klotho (alpha Kl) and the beta-klotho-associated protein fibroblast growth factor (FGF)-21 in men. Subjects consisted of apparently healthy men over 40 years of age who underwent health examination. Physical and biochemical parameters, including the levels of several cytokines and growth factors, were obtained from the subjects. Among middle-aged men (46.1 +/- 5.1 years), serum levels of FGF-21, soluble alpha Kl (s alpha Kl), and inflammation-related cytokine interleukin (IL)-6 were significantly higher in smokers than in never-smokers. Serum levels of FGF-21 increased and correlated with alanine transaminase, gamma guanosine-5'-triphosphate, and total cholesterol only in smokers, suggesting FGF-21 as a metabolic disorder-related factor in smokers. In aged men (60.3 +/- 1.7 years), although the serum levels of s alpha Kl in never-smokers were low, smokers showed highly increased serum levels of s alpha Kl. Serum levels of s alpha Kl was correlated with IL-6 in middle-aged never-smokers, suggesting s alpha Kl regulates IL-6. However, this correlation was disrupted in smokers and aged men.
  • 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 2326-5191 2015/08 [Refereed][Not invited]
     
    Objective. Interleukin-17 (IL-17)-producing T cells (Th17 cells) play critical roles in the pathogenesis of immune-related diseases, including systemic lupus erythematosus. However, the fundamental mechanism regulating Th17 cell differentiation is not fully understood. Recently, we demonstrated that plasma levels of CD147/basigin (Bsg) in patients with lupus nephritis (LN) were closely associated with disease activity. but the molecular mechanism involving Bsg has been elusive. Here, we addressed the role of Bsg in the pathogenesis of LN. Methods. Injections of pristane (2,6,10,14-tetramethylpentadecane [TMPD]) were administered to Bsg(-/-) or Bsg(+/+) mice to induce LN. The mice were killed 6 months after being injected, for histologic and biochemical analyses of the kidneys and spleens. Results. Pristane induced LN more strikingly in Bsg(-/-) mice than in Bsg(+/+) mice, even though humoral autoimmunity was similarly increased in both genotypes. The increased number of Th17, but not Th1, Treg cells, was augmented in Bsg(-/-) mice. The expression of IL-17 was also increased in the kidneys of Bsg(-/-) mice, in proportion to LN disease activity. Furthermore, treatment with anti-IL-17 antibody reduced LN disease activity in Bsg(-/-) mice. Complementary to these phenotypes of Bsg(-/-) mice, Bsg expression was enhanced in activated CD4+ T cells in vivo and in vitro. Bsg deficiency selectively augmented in vitro differentiation of naive CD4+ T cells to Th17 cells and STAT-3 phosphorylation during this differentiation. Moreover, STAT-3 phosphorylation was suppressed by crosslinking of Bsg with its antibody. Conclusion. Bsg plays an indispensable role in Th17 cell differentiation as a negative regulator by suppressing the IL-6/STAT-3 pathway.
  • 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 0022-1767 2015/08/01 [Refereed][Not invited]
     
    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.
  • 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 2050-084X 2015/08 [Refereed][Not invited]
     
    Although pain is a common symptom of various diseases and disorders, its contribution to disease pathogenesis is not well understood. Here we show using murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), that pain induces EAE relapse. Mechanistic analysis showed that pain induction activates a sensory-sympathetic signal followed by a chemokine-mediated accumulation of MHC class II+CD11b+ cells that showed antigen-presentation activity at specific ventral vessels in the fifth lumbar cord of EAE-recovered mice. Following this accumulation, various immune cells including pathogenic CD4+ T cells recruited in the spinal cord in a manner dependent on a local chemokine inducer in endothelial cells, resulting in EAE relapse. Our results demonstrate that a pain-mediated neural signal can be transformed into an inflammation reaction at specific vessels to induce disease relapse, thus making this signal a potential therapeutic target. DOI: 10.7554/eLife.08733.001
  • 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  2041-1723 2015/06 [Refereed][Not invited]
     
    KDEL receptors are responsible for retrotransporting endoplasmic reticulum (ER) chaperones from the Golgi complex to the ER. Here we describe a role for KDEL receptor 1 (KDELR1) that involves the regulation of integrated stress responses (ISR) in T cells. Designing and using an N-ethyl-N-nitrosourea (ENU)-mutant mouse line, T-Red (naive T-cell reduced), we show that a point mutation in KDELR1 is responsible for the reduction in the number of naive T cells in this model owing to an increase in ISR. Mechanistic analysis shows that KDELR1 directly regulates protein phosphatase 1 (PP1), a key phosphatase for ISR in naive T cells. T-Red KDELR1 does not associate with PP1, resulting in reduced phosphatase activity against eIF2 alpha and subsequent expression of stress responsive genes including the proapoptotic factor Bim. These results demonstrate that KDELR1 regulates naive T-cell homeostasis by controlling ISR.
  • 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 0027-8424 2015/05 [Refereed][Not invited]
     
    IL-6 is a multifunctional proinflammatory cytokine that is elevated in the serum of patients with pulmonary arterial hypertension (PAH) and can predict the survival of patients with idiopathic PAH (IPAH). Previous animal experiments and clinical human studies indicate that IL-6 is important in PAH; however, the molecular mechanisms of IL-6-mediated pathogenesis of PAH have been elusive. Here we identified IL-21 as a 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 up-regulated after hypoxia exposure in the lungs of mice treated with control antibody but not in the lungs of mice treated with MR16-1. Although 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. In accordance with these findings, IL-21 promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Of note, significantly enhanced expressions of IL-21 and M2 macrophage markers were detected in the lungs of IPAH patients who underwent lung transplantation. Collectively, these findings suggest that IL-21 promotes PAH in association with M2 macrophage polarization, downstream of IL-6-signaling. The IL-6/IL-21-signaling axis may be a potential target for treating PAH.
  • [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 0047-1852 2015/04 [Refereed][Not invited]
  • 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 0022-1767 2015/02 [Refereed][Not invited]
     
    In this study, we investigated the relationship between several growth factors and inflammation development. Serum concentrations of epiregulin, amphiregulin, betacellulin, TGF-alpha, fibroblast growth factor 2, placental growth factor (PLGF), and tenascin C were increased in rheumatoid arthritis patients. Furthermore, local blockades of these growth factors suppressed the development of cytokine-induced arthritis in mice by inhibiting chemokine and IL-6 expressions. We found that epiregulin expression was early and followed by the induction of other growth factors at different sites of the joints. The same growth factors then regulated the expression of epiregulin at later time points of the arthritis. These growth factors were increased in patients suffering from multiple sclerosis (MS) and also played a role in the development of an MS model, experimental autoimmune encephalomyelitis. The results suggest that the temporal expression of growth factors is involved in the inflammation development seen in several diseases, including rheumatoid arthritis and MS. Therefore, various growth factor pathways might be good therapeutic targets for various inflammatory diseases.
  • Ikuma Nakagawa, Daisuke Kamimura, Toru Atsumi, Yasunobu Arima, Masaaki Murakami
    CRITICAL REVIEWS IN IMMUNOLOGY 35 (5) 365 - 378 1040-8401 2015 [Refereed][Not invited]
     
    Inflammation is a fundamental response induced by the immune system to protect the body against pathogens, tissue damage, and stress. At the same time, recent studies have suggested that chronically induced inflammation is involved in various human diseases and disorders. Thus, understanding the molecular mechanisms of chronic inflammation could provide therapeutic value. Many mediators such as cytokines or chemokines regulate inflammatory responses. Among them, interleukin(IL)-6 is a prominent cytokine that induces and maintains inflammatory reactions. It is expressed by activated CD4+ T cells and also non-immune cells such as fibroblasts and epithelial cells. We discovered an inflammation-induction machinery, the inflammation amplifier, which is activated by the simultaneous stimulation of nuclear factor-kappa B (NF-kappa B) and signal transducers and activator of transcription 3 (STAT3) via various cytokines like IL-17 and IL-6 in non-immune cells. Activation of the inflammation amplifier induces a synergistic increase of IL-6, inflammatory chemokines, and growth factors. Using genome-wide screening, we identified several growth factors as mediators of the inflammation amplifier. In this review, we highlight the role of growth factors in the inflammation mechanism with special attention on the inflammation amplifier.
  • Huseby ES, Kamimura D, Arima Y, Parello CS, Sasaki K, Murakami M
    Frontiers in cellular neuroscience 9 295  2015 [Refereed][Not invited]
  • 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 0021-924X 2014/12 [Refereed][Not invited]
     
    The brain-blood barrier (BBB) tightly limits immune cell migration into the central nervous system (CNS), avoiding unwanted inflammation under the normal state. However, immune cells can traverse the BBB when inflammation occurs within the CNS, suggesting a certain signal that creates a gateway that bypasses the BBB might exist. We revealed the inflammation amplifier as a mechanism of this signal, and identified dorsal vessels of the fifth lumber (L5) spinal cord as the gateway. The inflammation amplifier is driven by a simultaneous activation of NF-kappa B and STATs in non-immune cells, causing the production of a large amount of inflammatory chemokines to open the gateway at L5 vessels. It was found that the activation of the amplifier can be modulated by neural activation and artificially operated by electric pulses followed by establishment of new gateways, Gateway Reflex, at least in mice. Furthermore, genes required for the inflammation amplifier have been identified and are highly associated with various inflammatory diseases and disorders in the CNS. Thus, physical and/or pharmacological manipulation of the inflammation amplifier holds therapeutic value to control neuro-inflammation.
  • 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 0027-8424 2014/08 [Refereed][Not invited]
     
    The humoral immune response, also called the antibody-mediated immune response, is one of the main adaptive immune systems. The essential micronutrient zinc (Zn) is known to modulate adaptive immune responses, and dysregulated Zn homeostasis leads to immunodeficiency. However, the molecular mechanisms underlying this Zn-mediated modulation are largely unknown. Here, we show that the Zn transporter SLC39A10/ZIP10 plays an important role in B-cell antigen receptor (BCR) signal transduction. Zip10-deficiency in mature B cells attenuated both T-cell-dependent and -independent immune responses in vivo. The Zip10-deficient mature B cells proliferated poorly in response to BCR cross-linking, as a result of dysregulated BCR signaling. The perturbed signaling was found to be triggered by a reduction in CD45R phosphatase activity and consequent hyperactivation of LYN, an essential protein kinase in BCR signaling. Our data suggest that ZIP10 functions as a positive regulator of CD45R to modulate the BCR signal strength, thereby setting a threshold for BCR signaling in humoral immune responses.
  • 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 2014/08 [Refereed][Not invited]
  • 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 0004-069X 2014/02 [Refereed][Not invited]
     
    Genome-wide analyses such as DNA microarray, RNA sequencing and RNA interference-based high-throughput screening are prevalent to decipher a biological process of interest, and provide a large quantity of data to be processed. An ultimate goal for researchers must be extrapolation of their data to human diseases. We have conducted functional genome-wide screenings to elucidate molecular mechanisms of the inflammation amplifier, a NF kappa B/STAT3-dependent machinery that potently drives recruitment of immune cells to promote inflammation. Using a public database of genome-wide association studies (GWAS), we recently reported the reverse-direction method by which our mass screening data were successfully linked to many human diseases. As an example, the epiregulin-epidermal growth factor receptor pathway was identified as a regulator of the inflammation amplifier, and associated with human diseases by GWAS. In fact, serum epiregulin levels were higher in patients with chronic inflammatory disorders. The reverse-direction method can be a useful tool to narrow mass data down to focus on human disease-related genes.
  • Yuki Mori, Masaaki Murakami, Yasunobu Arima, Dasong Zhu, Yasuo Terayama, Yutaka Komai, Yuji Nakatsuji, Daisuke Kamimura, Yoshichika Yoshioka
    INTERNATIONAL IMMUNOLOGY 26 (2) 93 - 101 0953-8178 2014/02 [Refereed][Not invited]
     
    Changes in the lower lumbar region during EAE are detectable by sensitive MRI.Magnetic resonance imaging (MRI) is widely employed for the diagnosis of multiple sclerosis (MS). However, sometimes, the lesions found by MRI do not correlate with the neurological impairments observed in MS patients. We recently showed autoreactive T cells accumulate in the fifth lumbar cord (L5) to pass the bloodbrain barrier and cause inflammation in the central nervous system of experimental autoimmune encephalomyelitis (EAE) mice, an MS model. We here investigated this early event using ultrahigh-field MRI. T2-weighted image signals, which conform to the water content, increased in L4 and L5 during the development of EAE. At the same time, the sizes of L4 and L5 changed. Moreover, angiographic images of MRI showed branch positions of the blood vessels in the lower lumbar cords were significantly altered. Interestingly, EAE mice showed occluded and thickened vessels, particularly during the peak phase, followed by reperfusion in the remission phase. Additionally, demyelination regions of some MS patients had increased lactic acid content, suggesting the presence of ischemic events. These results suggest that inflammation-mediated alterations in the lower lumbar cord change the homeostasis of the spinal cord and demonstrate that ultrahigh-field MRI enables the detection of previously invisible pathological alterations in EAE.
  • 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 0008-5472 2014/01 [Refereed][Not invited]
     
    Tumor-associated inflammation can induce various molecules expressed from the tumors themselves or surrounding cells to create a micro environment that potentially promotes cancer development. Inflammation, particularly chronic inflammation, is often linked to cancer development, even though its evolutionary role should impair nonself objects including tumors. The inflammation amplifier, a hyperinducer of chemokines in nonimmune cells, is the principal machinery for inflammation and is activated by the simultaneous stimulation of NF-kappa B and STAT3. We have redefined inflammation as local activation of the inflammation amplifier, which causes an accumulation of various immune cells followed by dysregulation of local homeostasis. Genes related to the inflammation amplifier have been genetically associated with various human inflammatory diseases. Here, we describe how cancer-associated genes, including interleukin (IL)-6, Ptgs2, ErbB1, Gas1, Serpine1, cMyc, and Vegf-alpha, are strongly enriched in genes related to the amplifier. The inflammation amplifier is activated by the stimulation of cytokines, such as TNF-alpha, IL-17, and IL-6, resulting in the subsequent expression of various target genes for chemokines and tumor-related genes like BCL2L11, CPNE7, FAS, HIF1-alpha, IL-1RAP, and SOD2. Thus, we conclude that inflammation does indeed associate with the development of cancer. The identified genes associated with the inflammation amplifier may thus make potential therapeutic targets of cancers. (C)2013 AACR.
  • Ogura H, Arima Y, Kamimura D, Murakami M
    Biomedical journal 6 36 269 - 273 2319-4170 2013/11 [Refereed][Not invited]
  • Kamimura D, Yamada M, Harada M, Sabharwal L, Meng J, Bando H, Ogura H, Atsumi T, Arima Y, Murakami M
    Frontiers in neuroscience 7 204  1662-4548 2013/10 [Refereed][Not invited]
  • 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 0953-8178 2013/05 [Refereed][Not invited]
     
    An IL-6-triggered NF-B loop: the IL-6 amplifier occurs in epithelia of a transplanted human lung.The IL-6 amplifier, a positive feedback loop for NFB signaling, which was originally found to be activated by IL-17A and IL-6 stimulation in non-immune cells, is molecularly a simultaneous activator of NFB and signal transducer and activator of transcription 3 (STAT3), functionally a local chemokine inducer and pathologically a machinery for inflammation development. It has been shown that IL-6 amplifier activation in epithelial cells contributes to rejection responses in a mouse chronic rejection model that develops a bronchiolitis obliterans (BO)-like disease. We investigated whether the IL-6 amplifier is activated in BO regions of a human lung graft after allogeneic transplantation. NFB and STAT3 molecules were phosphorylated in the epithelial regions of bronchi that localized in the BO regions. Additionally, chemokine ligand 2 (CCL2), and CD4 T cells and macrophages increased in these regions. Furthermore, human lung epithelial cells expressed CCL2 after stimulation by IFN in the presence of IL-6 and epidermal growth factor via enhanced STAT3 signaling, which parallels behavior seen in the mouse model. Thus, our results suggest that the IL-6 amplifier in the epithelial cells of grafts is involved in chronic rejection after lung transplantation, suggesting that the amplifier may be a valuable therapeutic target to prevent chronic rejection after lung transplantation.
  • Mari Sasaki, Akihiro Tojo, Yoshifumi Okochi, Nana Miyawaki, Daisuke Kamimura, Akihito Yamaguchi, Masaaki Murakami, Yasushi Okamura
    BIOCHEMICAL JOURNAL 450 295 - 301 0264-6021 2013/03 [Refereed][Not invited]
     
    H-v channels (voltage-gated proton channels) are expressed in blood cells, microglia and some types of epithelial cells. In neutrophils H-v channels regulate the production of reactive oxygen species through regulation of membrane potential and intracellular pH. H-v channels have also been suggested to play a role in sperm physiology in the human. However, the functions of the H-v channel at the whole-body level are not fully understood. In the present paper we show that Hvcn1 (voltage-gated hydrogen channel 1)-knockout mice show splenomegaly, autoantibodies and nephritis, that are reminiscent of human autoimmune diseases phenotypes. The number of activated T-cells was larger in Hvcn1-deficient mice than in the wild-type mice., Upon viral infection this was remarkably enhanced in Hvcn1-deficient mice. The production of superoxide anion in T-cells upon stimulation with PMA was significantly attenuated in the Hvcn1-deficient mice. These results suggest that H-v channels regulate T-cell homoeostasis in vivo.
  • Murakami M, Harada M, Kamimura D, Ogura H, Okuyama Y, Kumai N, Okuyama A, Singh R, Jiang JJ, Atsumi T, Shiraya S, Nakatsuji Y, Kinoshita M, Kohsaka H, Nishida M, Sakoda S, Miyasaka N, Yamauchi-Takihara K, Hirano T
    Cell reports 3 3 946 - 959 2013/03 [Refereed][Not invited]
  • 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 0022-1767 2013/01 [Refereed][Not invited]
     
    Extracellular ATP is released from live cells in controlled conditions, as well as dying cells in inflammatory conditions, and, thereby, regulates T cell responses, including Th17 cell induction. The level of extracellular ATP is closely regulated by ATP hydrolyzing enzymes, such as ecto-nucleoside triphosphate diphosphohydrolases (ENTPDases). ENTPDase1/CD39, which is expressed in immune cells, was shown to regulate immune responses by downregulating the ATP level. In this study, we analyzed the immunomodulatory function of ENTPDase7, which is preferentially expressed in epithelial cells in the small intestine. The targeted deletion of Entpd7 encoding ENTPDase7 in mice resulted in increased ATP levels in the small intestinal lumen. The number of Th17 cells was selectively increased in the small intestinal lamina propria in Entpd7(-/-) mice. Th17 cells were decreased by oral administration of antibiotics or the ATP antagonist in Entpd7(-/-) mice, indicating that commensal microbiota-dependent ATP release mediates the enhanced Th17 cell development in the small intestinal lamina propria of Entpd7(-/-) mice. In accordance with the increased number of small intestinal Th17 cells, Entpd7(-/-) mice were resistant to oral infection with Citrobacter rodentium. Entpd7(-/-) mice suffered from severe experimental autoimmune encephalomyelitis, which was associated with increased numbers of CD4(+) T cells producing both IL-17 and IFN-gamma. Taken together, these findings demonstrate that ENTPDase7 controls the luminal ATP level and, thereby, regulates Th17 cell development in the small intestine. The Journal of Immunology, 2013, 190: 774-783.
  • Arima Y, Kamimura D, Sabharwal L, Yamada M, Bando H, Ogura H, Atsumi T, Murakami M
    Mediators of inflammation 2013 898165  0962-9351 2013 [Refereed][Not invited]
  • Mori T, Ito Y, Yamazaki M, Murakami M, Noguchi S, Yamada N, Maruo K
    J Jpn Vet Med Assoc 66 (10) 709 - 712 2013 [Not refereed][Not invited]
  • 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 2013 [Not refereed][Not invited]
  • [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 0047-1852 2012/11 [Refereed][Not invited]
  • 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 4 189 (4) 1928 - 1936 0022-1767 2012/08 [Refereed][Not invited]
     
    The IL-6-amplifier first was discovered as a synergistic activation mechanism for NF-kappa B/STAT3 in type 1 collagen(+) cells. This process is marked by the hyperinduction of chemokines and subsequent local inflammation that leads to autoimmune diseases. In this study, we show that IL-6 amplifier activation in grafts plays important roles in allogeneic graft rejection by using a tracheal heterotopic transplantation model that includes bronchiolitis obliterans, a pathological marker for chronic rejection. IL-6, epidermal growth factor, and IFN-gamma all stimulate IL-6 amplifier activation, whereas CCL2, a chemotactic factor for Th1 cells, was one of the amplifier's main targets. Interestingly, IFN-gamma hyperinduced CCL2 in type 1 collagen(+) cells via the IL-6 amplifier at least in vitro. In addition, we detected IL-6, CCL2, phospho-STAT3, and phospho-NF-kappa B in epithelial type 1 collagen(+) cells of allogeneic tracheal grafts. These results show that IL-6 amplifier activation in grafts plays a critical role for graft rejection responses after allogeneic transplantation, including chronic rejection. From these results, we consider whether the IL-6 amplifier in grafts might be a valuable therapeutic target for the prevention of transplant rejection, including chronic rejection. The Journal of Immunology, 2012, 189: 1928-1936.
  • 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 0027-8424 2012/03 [Refereed][Not invited]
     
    Adequate activation of CD4(+) T lymphocytes is essential for host defense against invading pathogens; however, exaggerated activity of effector CD4(+) T cells induces tissue damage, leading to inflammatory disorders such as inflammatory bowel diseases. Several unique subsets of intestinal innate immune cells have been identified. However, the direct involvement of innate immune cell subsets in the suppression of T-cell-dependent intestinal inflammation is poorly understood. Here, we report that intestinal CX3C chemokine receptor 1(high) (CX(3)CR1(high)) CD11b(+) CD11c(+) cells are responsible for prevention of intestinal inflammation through inhibition of T-cell responses. These cells inhibit CD4(+) T-cell proliferation in a cell contact-dependent manner and prevent T-cell-dependent colitis. The suppressive activity is abrogated in the absence of the IL-10/Stat3 pathway. These cells inhibit T-cell proliferation by two steps. Initially, CX(3)CR1(high) CD11b(+) CD11c(+) cells preferentially interact with T cells through highly expressed intercellular adhesion molecule-1/vascular cell adhesion molecule-1; then, they fail to activate T cells because of defective expression of CD80/CD86. The IL-10/Stat3 pathway mediates the reduction of CD80/CD86 expression. Transfer of wild-type CX(3)CR1(high) CD11b(+) CD11c(+) cells prevents development of colitis in myeloid-specific Stat3-deficient mice. Thus, these cells are regulatory myeloid
  • 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 0092-8674 2012/02 [Refereed][Not invited]
     
    Although it is believed that neural activation can affect immune responses, very little is known about the neuroimmune interactions involved, especially the regulators of immune traffic across the blood-brain barrier which occurs in neuroimmune diseases such as multiple sclerosis (MS). Using a mouse model of MS, experimental autoimmune encephalomyelitis, we show that autoreactive T cells access the central nervous system via the fifth lumbar spinal cord. This location is defined by IL-6 amplifier-dependent upregulation of the chemokine CCL20 in associated dorsal blood vessels, which in turn depends on gravity-induced activation of sensory neurons by the soleus muscle in the leg. Impairing soleus muscle contraction by tail suspension is sufficient to reduce localized chemokine expression and block entry of pathogenic T cells at the fifth lumbar cord, suggesting that regional neuroimmune interactions may offer therapeutic targets for a variety of neurological diseases.
  • Masaaki Murakami, Toshio Hirano
    INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES 8 (9) 1267 - 1280 1449-2288 2012 [Refereed][Not invited]
     
    The NF kappa B-triggered positive feedback loop for IL-6 signaling in type 1 collagen+ non-immune cells (IL-6 amplifier) was first discovered to be a synergistic signal that is activated following IL-17A and IL-6 stimulation in type 1 collagen+ non-immune cells. Subsequent disease models have shown that it can also be stimulated by the simultaneous activation of NF kappa B and STAT3, functions as a local chemokine inducer, and acts as a mechanism for local inflammation, particularly chronic ones like rheumatoid arthritis and a multiple sclerosis. Moreover, we have recently shown that hyper activation of the IL-6 amplifier via regional neural activation establishes a gateway for immune cells including autoreactive T cells to pass the blood-brain barrier at dorsal vessels in 5th lumbar cord. Here we review how the IL-6 amplifier is activated by neural activation and the physiological relevance of the gateway to the central nervous system. Accumulating evidences continues to suggest that the IL-6 amplifier offers a potential molecular mechanism for the relationship between neural activation and the development of inflammatory diseases, which could establish a new interdisciplinary field that fuses neurology and immunology.
  • Masaaki Murakami, Toshio Hirano
    FRONTIERS IN IMMUNOLOGY 3 323  1664-3224 2012 [Refereed][Not invited]
  • Toshiyuki Fukada, Satoru Yamasaki, Keigo Nishida, Masaaki Murakami, Toshio Hirano
    JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY 16 (7) 1123 - 1134 0949-8257 2011/10 [Refereed][Not invited]
     
    The essential trace element zinc (Zn) is widely required in cellular functions, and abnormal Zn homeostasis causes a variety of health problems that include growth retardation, immunodeficiency, hypogonadism, and neuronal and sensory dysfunctions. Zn homeostasis is regulated through Zn transporters, permeable channels, and metallothioneins. Recent studies highlight Zn's dynamic activity and its role as a signaling mediator. Zn acts as an intracellular signaling molecule, capable of communicating between cells, converting extracellular stimuli to intracellular signals, and controlling intracellular events. We have proposed that intracellular Zn signaling falls into two classes, early and late Zn signaling. This review addresses recent findings regarding Zn signaling and its role in physiological processes and pathogenesis.
  • 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 5 187 (5) 2268 - 2277 0022-1767 2011/09 [Refereed][Not invited]
     
    Eosinophils are abundant in the lamina propria of the small intestine, but they rarely show degranulation in situ under steady-state conditions. In this study, using two novel mAbs, we found that intestinal eosinophils constitutively expressed a high level of an inhibitory receptor signal regulatory protein alpha (SIRP alpha)/CD172a and a low, but significant, level of a tetraspanin CD63, whose upregulation is closely associated with degranulation. Cross-linking SIRP alpha/CD172a on the surface of wild-type eosinophils significantly inhibited the release of eosinophil peroxidase induced by the calcium ionophore A23187, whereas this cross-linking effect was not observed in eosinophils isolated from mice expressing a mutated SIRP alpha/CD172a that lacks most of its cytoplasmic domain (SIRP alpha Cyto(-/-)). The SIRP alpha Cyto(-/-) eosinophils showed reduced viability, increased CD63 expression, and increased eosinophil peroxidase release with or without A23187 stimulation in vitro. In addition, SIRP alpha Cyto(-/-) mice showed increased frequencies of Annexin V-binding eosinophils and free MBP(+)CD63(+) extracellular granules, as well as increased tissue remodeling in the small intestine under steady-state conditions. Mice deficient in CD47, which is a ligand for SIRP alpha/CD172a, recapitulated these phenomena. Moreover, during Th2-biased inflammation, increased eosinophil cell death and degranulation were obvious in a number of tissues, including the small intestine, in the SIRP alpha Cyto(-/-) mice compared with wild-type mice. Collectively, our results indicated that SIRP alpha/CD172a regulates eosinophil homeostasis, probably by interacting with CD47, with substantial effects on eosinophil survival. Thus, SIRP alpha/CD172a is a potential therapeutic target for eosinophil-associated diseases. The Journal of Immunology, 2011, 187: 2268-2277.
  • Masaaki Murakami, Toshio Hirano
    FRONTIERS IN IMMUNOLOGY 2 22  1664-3224 2011 [Refereed][Not invited]
     
    It is commonly thought that autoimmune diseases are caused by the breakdown of self-tolerance, which suggests the recognition of specific antigens by autoreactive CD4+ T cells contribute to the specificity of autoimmune diseases (Marrack et al., 2001; Mathis and Benoist, 2004). In several cases, however, even for diseases associated with class II major histocompatibility complex (MHC) alleles, the causative tissue-specific antigens recognized by memory/activated CD4+ T cells have not been established (Mocci et al., 2000; Skapenko et al., 2005). Rheumatoid arthritis (RA) and arthritis in F759 knock-in mice (F759 mice) are such examples (Atsumi et al., 2002; Brennan et al., 2002; Falgarone 2009). These include associations with class II MHC and CD4 molecules; increased numbers of memory/activated CD4+ T cells; and improved outcomes in response to sup-pressions and/or deficiencies in class II MHC molecules, CD4+ T cells, and the T cell survival cytokine IL-7 Regarding the development of arthritis in F759 mice, it is not only the immune system, but also non-immune tissue that are involved, indicating that the importance of their interactions (Sawa et al., 2006, 2009; Ogura et al., 2008; Hirano, 2010; Murakami et al., 2011). Furthermore, we have shown that local events such as microbleeding together with an accumulation of activated CD4+ T cells in a manner independent of tissue antigen-recognitions induces arthritis in the joints of F759 mice (Murakami et al., 2011). For example, local microbleeding-mediated CCL20 expression induce such an accumulation, causing arthritis development via chronic activation of an IL-17A-dependent IL-6 signaling amplification loop in type 1 collagen+ cells that is triggered by CD4+ T cell-derived cytokine(s) such as IL-17A, which leads to the synergistic activation of STAT3 and NF kappa B in non-hematopoietic cells in the joint (Murakami et al., 2011). We named this loop the IL-6-mediated inflammation amplifier, or IL-6 amplifier for short (Ogura et al., 2008; Hirano, 2010; Murakami et al.,). Thus, certain class II MHC-associated, tissue-specific autoimmune diseases, including some RA subtypes, may be induced by local events that cause an antigen-independent accumulation of effector CD4+ T cells followed by the induction of the IL-6 amplifier in the affected tissue. In other words, in certain cases, the target tissue itself may determine the specificity of the autoimmune disease via activation of the IL-6 amplifier. To explain this hypothesis, we have proposed a four-step model for MHC class II-associated autoimmune diseases (Murakami et al., 2011): (1)T cell activation regardless of antigen specificity; (2) local events inducing a tissue-specific accumulation of activated T cells; (3) transient activation of the IL-6 amplifier; and (4) enhanced sensitivity to cytokines in the target tissue. The interaction of these events results in chronic activation of the IL-6 amplifier and subsequent manifestation of autoimmune diseases. Thus, the IL-6 amplifier, which is chronically activated by these four events, is a critical regulator of chronic inflammations in tissue-specific MHC class II-associated autoimmune diseases.
  • 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 0022-1007 2011/01 [Refereed][Not invited]
     
    Cognate antigen recognition by CD4(+) T cells is thought to contribute to the tissue specificity of various autoimmune diseases, particularly those associated with class II MHC alleles. However, we show that localized class II MHC-dependent arthritis in F759 mice depends on local events that result in the accumulation of activated CD4(+) T cells in the absence of cognate antigen recognition. In this model, transfer of in vitro polarized Th17 cells combined with the induction of experimental microbleeding resulted in CCL20 production, the accumulation of T cells in the joints, and local production of IL-6. Disease induction required IL-17A production by transferred T cells, IL-6 and CCL20 expression, and STAT3 signaling in type I collagen-expressing cells. Our data suggest a model in which the development of autoimmune disease in F759 mice depends on four events: CD4(+) T cell activation regardless of antigen specificity, local events that induce T cell accumulation, enhanced sensitivity to T cell-derived cytokines in the tissue, and activation of IL-6 signaling in the tissue. This model provides a possible explanation for why tissue-specific antigens recognized by activated CD4(+) T cells have not been identified in many autoimmune diseases, especially those associated with class II MHC molecules.
  • 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 0953-8178 2010/05 [Refereed][Not invited]
     
    Zinc (Zn) is an essential trace metal required by many enzymes and transcription factors for their activity or the maintenance of their structure. Zn has a variety of effects in the immune responses and inflammation, although it has not been well known how Zn affects these reactions on the molecular basis. We here showed that Zn suppresses T(h)17-mediated autoimmune diseases at lest in part by inhibiting the development of T(h)17 cells via attenuating STAT3 activation. In mice injected with type II collagen to induce arthritis, Zn treatment inhibited T(h)17 cell development. IL-6-mediated activation of STAT3 and in vitro T(h)17 cell development were all suppressed by Zn. Importantly, Zn binding changed the alpha-helical secondary structure of STAT3, disrupting the association of STAT3 with JAK2 kinase and with a phospho-peptide that included a STAT3-binding motif from the IL-6 signal transducer gp130. Thus, we conclude that Zn suppresses STAT3 activation, which is a critical step for T(h)17 development.
  • Takayuki Nakagawa, Mineko Tsuruoka, Hideki Ogura, Yuko Okuyama, Yasunobu Arima, Toshio Hirano, Masaaki Murakami
    INTERNATIONAL IMMUNOLOGY 22 (2) 129 - 139 0953-8178 2010/02 [Refereed][Not invited]
     
    Although recent studies have identified regulatory roles for Foxp3(+)CD8(+) T cells, the mechanisms that induce their development and underlie their functions in vivo have not been elucidated. Here, we show that IL-6 positively regulates the Foxp3(+)CD8(+) T-cell development and function. The Foxp3(+)CD8(+) T cells that differentiated in vitro in the presence of IL-6 suppressed autoimmune colitis and arthritis in vivo. Moreover, Foxp3(+)CD8(+) T cells that developed in vivo in the presence of enhanced IL-6 signaling suppressed the development of a spontaneous T(h)17 cell-mediated autoimmune arthritis. Thus, we concluded that Foxp3(+)CD8(+) T cells develop in response to IL-6 and regulate chronic inflammation in T(h)17 cell-mediated F759 autoimmune arthritis. These results suggested that Foxp3(+)CD8(+) T cells may develop in response to IL-6 under certain inflammatory conditions in vivo and may regulate some other chronic inflammation diseases.
  • Yukihisa Sawa, Yasunobu Arima, Hideki Ogura, Chika Kitabayashi, Jing-Jing Jiang, Toru Fukushima, Daisuke Kamimura, Toshio Hirano, Masaaki Murakami
    IMMUNITY 30 (3) 447 - 457 1074-7613 2009/03 [Refereed][Not invited]
     
    Systemic cytokine activity in response to Toll-like receptor (TLR) signaling induces the expression of various proteins in the liver after infections. Here we show that Interleukin-7 (IL-7), the production of which was thought to occur at a constant rate in vivo, was a hepatically expressed protein that directly controled T cell responses. Depletion of IL-7 expression in the liver abrogated several TLR-mediated T cell events, including enhanced CD4(+) T cell and CD8(+) T cell survival, augmented CD8(+) T cell cytotoxic activity, and the development of experimental autoimmune encephalitis, a Th17 cell-mediated autoimmune disease. Thus, T cell responses are regulated by hepatocyte-derived IL-7, which is expressed in response to TLR signaling in vivo. We suggested that TLR-induced IL-7 expression in the liver, which is an acute-phase response, may be a good diagnostic and therapeutic target for efficient vaccine developments and for conditions characterized by TLR-mediated T cell dysregulation, including autoimmune diseases.
  • 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 0953-8178 2009/01 [Refereed][Not invited]
     
    Infection with pathogens containing superantigens (Sags) can result in massive excessive CD4(+) T cell activation and death in such conditions as toxic shock, food poisoning and autoimmune diseases. We here showed how enhancement of IL-6 signaling suppresses Sag-mediated activated CD4(+) T cell death. Sag-induced CD4(+) T cell death increased in IL-6 knockout (KO) mice, whereas it decreased in mice characterized by enhanced IL-6-gp130-STAT3 signaling. The serum concentration of IFN-gamma was inversely correlated with the magnitude of IL-6 signaling, and IFN-gamma deficiency inhibited Sag-induced activated CD4(+) T cell death, suggesting that IL-6 suppresses CD4(+) T cell death via IFN-gamma expression. Interestingly, depletion of activated CD8(+) T cells inhibited Sag-mediated increases in IFN-gamma expression in IL-6 KO mice as well as the augmented CD4(+) T cell death. The results demonstrate that IL-6-gp130-STAT3 signaling in activated CD8(+) T cells contributes to Sag-induced CD4(+) T cell death via IFN-gamma expression, highlighting this signaling axis in CD8(+) T cells as a potential therapeutic target for Sag-related syndromes.
  • Nakayama M, Mori T, Iwatani N, Sakai H, Murakami M, Sato A, Maruo K
    J Jpn Vet Med Assoc 62 (5) 395 - 397 2009 [Not refereed][Not invited]
  • Hideki Ogura, Masaaki Murakami, Yuko Okuyama, Mineko Tsuruoka, Chika Kitabayashi, Minoru Kanamoto, Mika Nishihara, Yoichiro Iwakura, Toshio Hirano
    IMMUNITY 29 (4) 628 - 636 1074-7613 2008/10 [Refereed][Not invited]
     
    Dysregulated cytokine expression and signaling are major contributors to a number of autoimmune diseases. Interleukin-17A (IL-17A) and IL-6 are important in many disorders characterized by immune self-recognition, and IL-6 is known to induce the differentiation of T helper 17 (Th17) cells. Here we described an IL-17A-triggered positive-feed back loop of IL-6 signaling, which involved the activation of the transcription factors nuclear factor (NF)-kappa B and signal transducer and activator of transcription 3 (STAT3) in fibroblasts. Importantly, enhancement of this loop caused by disruption of suppressor of cytokine signaling 3 (SOCS3)-dependent negative regulation of the IL-6 signal transducer gp130 contributed to the development of arthritis. Because this mechanism also enhanced experimental autoimmune encephalomyelitis (EAE) in wild-type mice, it may be a general etiologic process underlying other Th17 cell-mediated autoimmune diseases.
  • Yoshinori Tanaka, Nobuyuki Tanaka, Yasushi Saeki, Keiji Tanaka, Masaaki Murakami, Toshio Hirano, Naoto Ishii, Kazuo Sugamura
    MOLECULAR AND CELLULAR BIOLOGY 28 (15) 4805 - 4818 0270-7306 2008/08 [Refereed][Not invited]
     
    Interieukin 6 (IL-6), a pleiotropic cytokine, functions in cells through its interaction with its receptor complex, which consists of two ligand-binding alpha subunits and two signal-transducing subunits known as gp130. There is a wealth of studies on signals mediated by gp130, but its downregulation is less well understood. Here we found that IL-6 stimulation induced lysosome-dependent degradation of gp130, which correlated with an increase in the K63-linked polyubiquitination of gp130. The stimulation-dependent ubiquitination of gp130 was mediated by c-Cb1, an E3 ligase, which was recruited to gp130 in a tyrosine-phosphorylated SHP2-dependent manner. We also found that IL-6 induced a rapid translocation of gp130 from the cell surface to endosomal compartments. Furthermore, the vesicular sorting molecule Hrs contributed to the lysosomal degradation of gp130 by directly recognizing its ubiquitinated form. Deficiency of either Hrs or c-Cbl suppressed gp130 degradation, which leads to a prolonged and amplified IL-6 signal. Thus, our present report provides the first evidence for involvement of a c-Cbl/SHP2 complex in ubiquitination and lysosomal degradation of gp130 upon IL-6 stimulation. The lysosomal degradation of gp130 is critical for cessation of IL-6-mediated signaling.
  • Masaaki Murakami, Toshio Hirano
    CANCER SCIENCE 99 (8) 1515 - 1522 1347-9032 2008/08 [Refereed][Not invited]
     
    Zinc (Zn) is an essential heavy metal that is incorporated into a number of human Zn metalloproteins. Zn plays important roles in nucleic acid metabolism, cell replication, and tissue repair and growth. Zn deficiency is associated with a range of pathological conditions, including impaired immunity, retarded growth, brain development disorders and delayed wound healing. Moreover, many reports have suggested that Zn is involved in cancer development and levels of Zn in serum and malignant tissues of patients with various types of cancer are abnormal. Zn may directly affect tumor cells by regulating gene expression profiles and/or cell viability, both of which are mediated in part by tumor-induced changes in Zn transporter expression. On the other hand, Zn may indirectly influence tumor cells by affecting processes within the cancer microenvironment, including immune responses; the functions and/or activity levels of immune cells that attack tumor cells are influenced by the intracellular Zn concentrations within those cells. In both cases, Zn contributes to intracellular metal homeostasis and/or signal transduction in tumor and immune cells. In this review article, we will summarize the current understanding of the roles of Zn homeostasis and signaling primarily in immune cells, with a discussion of the contributions of these processes to oncogenesis. (Cancer Sci 2008; 99: 1515-1522)
  • Gui-Hua Jin, Toshio Hirano, Masaaki Murakami
    INTERNATIONAL IMMUNOLOGY 20 (6) 783 - 789 0953-8178 2008/06 [Refereed][Not invited]
     
    Combination treatment consisting of IL-2 together with anti-IL-2 mAbs results in markedly larger increases in the numbers of CD8(+) T cells, dendritic cells (DCs) and NK cells in vivo compared with the results observed with injections of IL-2 or the antibodies alone. We previously showed that this combination treatment overcomes the problems associated with the short half-life of IL-2 in vivo. Importantly, the combination treatment but not IL-2 or the anti-IL-2 mAbs alone protected the mice against tumor metastases in the lungs. Here we have investigated which cell types are responsible for this protective immunity against tumors. We analyzed tumor metastases in mice that were depleted of DCs, CD8(+) T cells or NK cells. DC-deficient, diphtheria toxin receptor-expressing mice injected with diphtheria toxin as well as B cell- and T cell-deficient RAG-2-knockout mice were protected against tumors after they were administered the combination treatment. On the other hand, mice that were depleted of NK cells using anti-asialo-GM1 antibodies did not exhibit the anti-tumor activity after treatment with IL-2 combined with anti-IL-2 mAbs. Thus, these data demonstrate that NK cells, but not DCs, or CD8(+) T cells mediate the anti-tumor effect induced by this combination treatment. Therefore, combining neutralizing anti-IL-2 mAbs with IL-2 may be clinically useful to effectively enhance IL-2-mediated NK cell activities.
  • Toshio Hirano, Masaaki Murakami, Toshiyuki Fukada, Keigo Nishida, Satoru Yamasaki, Tomoyuki Suzuki
    ADVANCES IN IMMUNOLOGY, VOL 97 97 149 - 176 0065-2776 2008 [Refereed][Not invited]
     
    Zinc (Zn) is an essential nutrient required for cell growth, differentiation, and survival, and its deficiency causes growth retardation, immunodeficiency, and other health problems. Therefore, Zn homeostasis must be tightly controlled in individual cells. Zn is known to be important in the immune system, although its precise roles and mechanisms have not yet been resolved. Zn has been suggested to act as a kind of neurotransmitter. In addition, Zn has been shown to bind and affect the activity of several signaling molecules, such as protein tyrosine phosphatases (PTPs). However, it has not been known whether Zn itself might act as an intracellular signaling molecule, that is, a molecule whose intracellular status is altered in response to an extracellular stimulus, and that is capable of transducing the extracellular stimulus into an intracellular signaling event. Here we propose that Zn acts as a signaling molecule and that there are at least two kinds of Zn signaling: "late Zn signaling," which is dependent on a change in the expression profile of Zn transporters, and "early Zn signaling," which involves a "Zn wave" and is directly induced by an extracellular stimulus. We also review recent progress in uncovering the roles of Zn in the immune system.
  • Takagi M, Watanabe K, Mori T, Kondo M, Murakami M, Masegi T, Yamazoe K, Kudo T
    J Jpn Vet Med Assoc 61 (3) 215 - 218 2008 [Not refereed][Not invited]
  • 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 0953-8178 2007/06 [Refereed][Not invited]
     
    IL-17-producing T-h (T(h)17) comprise a distinct lineage of pro-inflammatory T-h that are major contributors to autoimmune diseases. Treatment with IL-6 and transforming growth factor beta (TGF beta) induces naive CD4(+) T cells to generate Th17, which also requires expression of the IL-6/TGF[3 target ROR gamma t. We reported that IL-6 transduces two signaling pathways via tyrosine redidues of the signal transducer gp130: one depends on signal transducers and activators of transcription (STAT)-3 activation and the other on Src homology region 2 domain-containing phosphatase 2 (SHP2)/Grb2 associated binder (Gab)/mitogen-activated protein kinase (MAPK) activation. Here, we showed that CD4+ T cells carrying a mutant gp130 that transduces the SHP2/Gab/MAPK pathway but not the STAT3-mediated one failed to develop into Th17, while CD4+ T cells whose mutant gp130 transduces the STAT3 signal only generated Th17, indicating that IL-6 acts directly on T cells through the tyrosine residues of gp130 required for STAT3 activation to promote the development of Th17. Moreover, we found that gp130-STAT3 pathway is essential for Th17 development and for the expression of ROR gamma t by using T cells specifically lacking gp130 and STAT3. Noteworthy is that the regulatory T cell (Treg) percentages and numbers were comparable between all mutant mice we tested in vivo, although we showed that IL-6-gp130-STAT3 pathway suppressed Treg development in vitro. Thus, we conclude that IL-6 acts directly to promote the development of Th17 by activating the T cell gp130-STAT3 pathway but has a minimum effect on Treg development at least in the steady state in vivo. Therefore, blockade of IL-6-gp130-STAT3 pathway in CD4+ T cells could be a good target for controlling unwanted T(h)17-mediated immune responses including autoimmune diseases.
  • 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 0021-9738 2007/05 [Refereed][Not invited]
     
    Patients with Omenn syndrome (OS) have hypomorphic RAG mutations and develop varying manifestations of severe combined immunodeficiency. It is not known which symptoms are caused directly by the RAG mutations and which depend on other polymorphic genes. Our current understanding of OS is limited by the lack of an animal model. In the present study, we identified a C57BL/10 mouse with a spontaneous mutation in, and reduced activity of, RAG1. Mice bred from this animal contained high numbers of memory-phenotype T cells and experienced hepatosplenomegaly and eosinophilia, had oligoclonal T cells, and demonstrated elevated levels of IgE, major symptoms of OS. Depletion of CD4(+) T cells in the mice caused a reduction in their IgE levels. Hence these "memory mutant" mice are a model for human OS; many symptoms of their disease were direct results of the Rag hypomorphism and some were caused by malfunctions of their CD4(+) T cells.
  • Khiong Khie, Murakami Masaaki, Kitabayashi Chika, Ueda Naoko, Sawa Shin-ichiro, Sakamoto Akemi, Kotzin L Brian, Rozzo J Stephen, Ishihara Katsuhiko, Verella-Garcia Marileila, Kappler John, Marrack Philippa, Hirano Toshio
    The Journal of Clinical Investigation 117 (5) 1270-1281  1558-8238 2007/05 [Refereed][Not invited]
     
    オーメン症候群のマウスモデルでは、CD4T細胞のホメオスタテイック増殖が病因に関与している。
  • 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 1529-2908 2006/09 [Refereed][Not invited]
     
    Zinc is a trace element that is essential for the function of many enzymes and transcription factors. Zinc deficiency results in defects in innate and acquired immune responses. However, little is known about the mechanism(s) by which zinc affects immune cell function. Here we show that stimulation with the Toll-like receptor 4 agonist lipopolysaccharide (LPS) altered the expression of zinc transporters in dendritic cells and thereby decreased intracellular free zinc. A zinc chelator mimicked the effects of LPS, whereas zinc supplementation or overexpression of the gene encoding Zip6, a zinc transporter whose expression was reduced by LPS, inhibited LPS-induced upregulation of major histocompatibility complex class II and costimulatory molecules. These results establish a link between Toll-like receptor signaling and zinc homeostasis.
  • 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 0953-8178 2006/09 [Refereed][Not invited]
     
    CD1d-restricted NKT cells are activated by TCR-mediated stimulation via CD1d plus lipid antigens such as alpha-galactosylceramide (alpha-GaICer). These cells suppressed autoimmunity and graft rejection, but sometimes enhanced resistance to infection and tumor immunity. This double-action phenomenon of NKT cells is partly explained by cytokines produced by NKT cells. Therefore, roles of cytokines from activated NKT cells have been extensively examined; however, their roles on T cell homeostatic proliferation in lymphopenic condition have not been investigated. Here, we showed that alpha-GaICer enhanced homeostatic proliferation of CD8(+) but not CD4(+) T cells and this effect of alpha-GaICer was required for NKT cells. IL-4 was essential and sufficient for this NKT cell action on CD8(+) T cell homeostatic proliferation. Importantly, the expression of IL-4R alpha and STAT6 in CD8(+) T cells was essential for the NKT activity, indicating a direct action of IL-4 on CD8(+) T cells. Consistent with this, the level of IL-4R alpha expression on memory phenotype CD8(+) T cells was higher than that on naive phenotype one and CD4(+) T cells. Thus, these results showed the 'involvement' of IL-4 that is produced from activated NKT cells for CD8(+) T cell homeostatic proliferation in vivo.
  • 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 0261-4189 2006/09 [Refereed][Not invited]
     
    Dendritic cells (DC) play a central role in immune responses by presenting antigenic peptides to CD(4+) T cells through MHCII molecules. Here, we demonstrate a TRIF-GEFH1-RhoB pathway is involved in MHCII surface expression on DC. We show the TRIF (TIR domain-containing adapter inducing IFN beta)- but not the myeloid differentiation factor 88 (MyD88)-dependent pathway of lipopolysaccharide (LPS)-signaling in DC is crucial for the MHCII surface expression, followed by CD(4+) T-cell activation. LPS increased the activity of RhoB, but not of RhoA, Cdc42, or Rac1/2 in a manor dependent on LPS-TRIF- but not LPS-Myd88-signaling. RhoB colocalized with MHCII+ lysosomes in DC. A dominant-negative (DN) form of RhoB (DN-RhoB) or RhoB's RNAi in DC inhibited the LPS-induced MHCII surface expression. Moreover, we found GEFH1 associated with RhoB, and DN-GEFH1 or GEFH1's RNAi suppressed the LPS-mediated RhoB activation and MHCII surface expression. DN-RhoB attenuated the DC's CD(4+) T-cell stimulatory activity. Thus, our results provide a molecular mechanism relating how the MHCII surface expression is regulated during the maturation stage of DC. The activation of GEFH1-RhoB through the TRIF-dependent pathway of LPS in DC might be a critical target for controlling the activation of CD4+ T cells.
  • Masato Murakami, Shinobu Iwai, Sachie Hiratsuka, Mai Yamauchi, Kazuhide Nakamura, Yoichiro Iwakura, Masabumi Shibuya
    BLOOD 108 (6) 1849 - 1856 0006-4971 2006/09 [Refereed][Not invited]
     
    Vascular endothelial growth factor (VEGF) and VEGF receptor-1 (VEGFR-1/Flt-1) were shown to be involved in pathological angiogenesis, particularly rheumatoid arthritis (RA). However, the molecular basis of their actions is not fully understood. Here we report that in a murine model of RA, deletion of the tyrosine kinase (TK) domain of VEGFR-1 decreased the incidence and clinical symptoms of RA. Pathological symptoms, such as synovial hyperplasia, inflammatory infiltrates, pannus formation, and cartilage/bone destruction, became milder in Vegfr-1 tk(-/-) mice compared with wild-type (Wt) mice in the human T-cell leukemia virus-1 (HTLV-1) pX-induced chronic models. VEGFR-1 TK-deficient bone marrow cells showed a suppression of multilineage colony formation. Furthermore, macrophages induced to differentiate in vitro showed a decrease in immunologic reactions such as phagocytosis and the secretion of interleukin-6 (IL-6) and VEGF-A. Treatment of this RA model with a small molecule inhibitor for VEGFR TK, KRN951, also attenuated the arthritis. These results indicate that the VEGFR-1 TK signaling modulates the proliferation of bone marrow hematopoietic cells and immunity of monocytes/macrophages and promotes chronic inflammation, which may be a new target in the treatment of RA.
  • 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 0022-1767 2006/07 [Refereed][Not invited]
     
    IL-2 is a potent immunostimulant and has been tested for clinical use, including in immunotherapy for cancers and HIV infection. Here we show that a widely used neutralizing anti-murine IL-2 mAb (S4B6) exhibits unexpected activities that enhance the treatment effects of IL-2 in vivo. Coinjection of the anti-IL-2 mAb with a plasmid carrying murine IL-2 eDNA significantly increased the serum IL-2 levels and induced a substantial increase in the division of CD8(+) T and NK1.1(high) cells in vivo. Injection of the mAb premixed with recombinant murine IL-2 showed the same enhanced effect. A 5-day treatment with the anti-IL-2 mAb alone gradually increased the CD44(high)CD8(+) population, and the increased population was maintained for > 300 days, suggesting that the mAb can gradually maintain and potentially enhance the bioactivity of endogenous IL-2 for extended periods. Furthermore, combined treatment with the anti-IL-2 mAb plus the IL-2 plasmid markedly enhanced Ag-specific CTL activity in vivo and partially protected mice from tumor metastasis to the lungs, compared with the anti-IL-2 mAb or IL-2 plasmid alone. These results demonstrated IL-2-enhancing effects of the anti-IL-2 mAb in vivo and suggest that combining a neutralizing anti-IL-2 Ab with IL-2 gene delivery might be used effectively to enhance IL-2 functions in clinical applications.
  • 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 0022-1007 2006/06 [Refereed][Not invited]
     
    Mice homozygous for the F759 mutation in the gp130 interleukin ( IL)-6 receptor subunit have enhanced gp130-mediated signal transducer and activator of transcription ( STAT)3 activation and spontaneously developed a lymphocyte-mediated rheumatoid arthritis-like joint disease. Here, we show that the development of the disease is dependent on both major histocompatibility complex ( MHC)II-restricted CD4(+) T cells and IL-6 family cytokines. In spite of the necessity for CD4(+) T cells, the gp130 mutation was only required in nonhemtopoietic cells for the disease. The gp130 mutation resulted in enhanced production of IL-7. Conditional knockout of STAT3 in nonlymphoid cells showed that the enhancement of IL-7 production was dependent on STAT3 activation by IL-6 family cytokines. Homeostatic proliferation of CD4(+) T cells was enhanced in gp130 mutant mice and acceleration of homeostatic proliferation enhanced the disease, whereas the inhibition of homeostatic proliferation suppressed the disease. Anti-IL-7 antibody treatment inhibited not only the enhanced homeostatic proliferation, but also the disease in gp130 mutant mice. Thus, our results show that autoimmune disease in gp130 mutant mice is caused by increased homeostatic proliferation of CD4(+) T cells, which is due to elevated production of IL-7 by nonhematopoietic cells as a result of IL-6 family cytokine-gp130-STAT3 signaling.
  • T Hirano, M Murakami
    DEVELOPMENTAL CELL 10 (5) 542 - 544 1534-5807 2006/05 [Refereed][Not invited]
     
    Signaling via suppressors of cytokine signaling (SOCS) is an important negative feedback system for cytokine-mediated signal transduction. Recently in Molecular Cell, Babon et al. (2006) described the tertiary structure of SOCS3 in complex with a phosphotyrosine-containing peptide from the IL-6 receptor sub-unit gp130, and they identified the specific amino acids that are critical for binding.
  • H Kitamura, H Kamon, SI Sawa, SJ Park, N Katunuma, K Ishihara, M Murakami, T Hirano
    IMMUNITY 23 (5) 491 - 502 1074-7613 2005/11 [Refereed][Not invited]
     
    We found IL-6-STAT3 pathway suppresses MHC class II (MHCII) expression on dendritic cells (DCs) and attenuates T cell activation. Here, we showed that IL-6-STAT3 signaling reduced intracellular MHCII alpha beta dimmer, Ii, and H2-DM levels in DCs. IL-6-mediated STAT3 activation decreased cystatin C level, an endogenous inhibitor of cathepsins, and enhanced cathepsin activities. Importantly, cathepsin S inhibitors blocked reduction of MHCII alpha beta dimer, Ii, and H2-DM in the IL-6-treated DCs. Overexpression of cystatin C suppressed IL-6-STAT3-mediated increase of cathepsin S activity and reduction of MHCII alpha beta dimer, Ii, and H2-DM levels in DCs. Cathepsin S overexpression in DCs decreased intracellular MHCII alpha beta dimer, Ii, and H2-DM levels, LPS-mediated surface expression of MHCII and suppressed CD4(+) T cell activation. IL-6-gp130-STAT3 signaling in vivo decreased cystatin C expression and MHCII alpha beta dimer level in DCs. Thus, IL-6-STAT3-mediated increase of cathepsin S activity reduces the MHCII alpha beta dimer, Ii, and H2-DM levels in DCs, and suppresses CD4(+) T cell-mediated immune responses.
  • Murakami M, Sawa S-I, Kamimura D, Kamon H, Kitamura H, Kawabe T, Park S-J, Ishihara K, Hirano T
    International Congress Series 1285 207 - 211 2005/11 [Refereed][Not invited]
  • [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 0047-1852 2005/04 [Refereed][Not invited]
  • T Mori, M Murakami, M Okumura, T Kadosawa, T Uede, T Fujinaga
    JOURNAL OF VETERINARY MEDICAL SCIENCE 67 (1) 51 - 56 0916-7250 2005/01 [Refereed][Not invited]
     
    In order to analyze the detailed mechanisms responsible for macrophage activation by chitin derivatives, resident peritoneal macrophages were prepared and stimulated with chitin, chitosan and low-molecular weight chitosan. Our findings were as follows: (i) chitosan induced apoptosis of peritoneal macrophages, but this did not occur when chitin or water soluble low-molecular weight chitosan were used; (ii) chitosan treatment induced activation markers, such as the major histocompatibility complex (MHC) class I, class II, Fc receptors, transferrin receptor, mannose receptor, Fas, and macrophage inflammatory protein (MIP)-2, whereas chitin and low molecular weight soluble chitosan induced only the expression of MHC class I and 11 molecules; (iii) apoptosis induced by chitosan was mediated by the Fas signaling pathway, in response to phagocytosis via the mannose receptor. We conclude that since chitosan activates macrophages, this may be the mechanism by which it accelerates wound healing.
  • 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 0022-1767 2004/11 [Refereed][Not invited]
     
    The homeostasis of memory CD8(+) T cells is regulated by cytokines. IL-15 is shown to promote the proliferation of memory CD8(+) T cells, while IL-2 suppresses their division in vivo. This inhibitory effect of IL-2 appears to occur indirectly, through other cell populations including CD25(+)CD4(+) T cells; however, the details of this mechanism remain unclear. In this study, we show that 1) both Ag-experienced and memory phenotype CD8(+) T cells divided after the depletion of IL-2 in vivo; 2) this division occurred normally and CD44(high)IL-2/15Rbeta(high) CD8(+) T cells generated after IL-2 depletion in IL-15 knockout (KO) and in IL-7-depleted IL-15 KO mice; 3) surprisingly, the blockade of IL-2/15Rbeta signaling in IL-2-depleted IL-15 KO mice completely abolished the division of memory CD8(+) T cells, although the only cytokines known to act through IL-2/15Rbeta are IL-2 and IL-15; and 4) the expression of IL-2/15Rbeta molecules on memory CD8(+) T cells was required for their division induced by IL-2 depletion. These results demonstrate that the depletion of IL-2 in vivo induced memory CD8(+) T cell division by an IL-15-independent but by an IL-2/15Rbeta-dependent mechanism, suggesting the existence of a novel IL-2/15Rbeta-utilizing cytokine that acts directly on memory CD8(+) T cells to promote cell division.
  • 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 0022-1767 2004/09 [Refereed][Not invited]
     
    Dendritic cells (DCs) orchestrate immune responses according to their state of maturation. In response to infection, DCs differentiate into mature cells that initiate immune responses, while in the absence of infection, most of them remain in an immature form that induces tolerance to self Ags. Understanding what controls these opposing effects is an important goal for vaccine development and prevention of unwanted immune responses. A crucial question is what cytokine(s) regulates DC maturation in the absence of infection. In this study, we show that IL-6 plays a major role in maintaining immature DCs. IL-6 knockout (KO) mice had increased numbers of mature DCs, indicating that IL-6 blocks DC maturation in vivo. We examined this effect further in knockin mice expressing mutant versions of the IL-6 signal transducer gp130, with defective signaling through either Src homology region 2 domain-containing phosphatase 2/Gab/MAPK (gp130 (F759/F759)) or STAT3 (gp130(FxxQ/FxxQ)), and combined gp130 and IL-6 defects (gp130(F759/F759)/IL-6 KO mice). Importantly, we found STAT3 activation by IL-6 was required for the suppression of LPS-induced DC maturation. In addition, STAT3 phosphorylation in DCs was regulated by IL-6 in vivo, and STAT3 was necessary for the IL-6 suppression of bone marrow-derived DC activation/maturation. DC-mediated T cell activation was enhanced in IL-6 KO mice and suppressed in gp130(F759/F759) mice. IL-6 is thus a potent regulator of DC differentiation in vivo, and IL-6-gp130-STAT3 signaling in DCs may represent a critical target for controlling T cell-mediated immune responses in vivo.
  • M Murakami, D Kamimura, T Hirano
    GROWTH FACTORS 22 (2) 75 - 77 0897-7194 2004/06 [Refereed][Not invited]
  • 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 0953-8178 2004/03 [Refereed][Not invited]
     
    Rheumatoid arthritis (RA) is a polygenic autoimmune disease. The autoimmunity develops from synergistic actions of genetic and environmental factors. We generated a double-mutant mouse by crossing two murine models of RA, a gp130 mutant knock-in mouse (gp130(F759/F759)) and an HTLV-1 pX transgenic mouse (pX-Tg), in a C57BL/6 background, which is resistant to arthritis. The mice spontaneously developed severe arthritis with a much earlier onset than the gp130(F759/F759) mice and with a much higher incidence than did the pX-Tg mice. The symptoms of gp130(F759/F759) mice, including lymphoadenopathy, splenomegaly, hyper-gamma-globulinemia, autoantibody production, increases in memory/activated T cells and granulocytes in the peripheral lymphoid organs, and a decrease in the class II MHCbright CD11c(+) population, were augmented in the double mutants. Marked reductions in incidence, severity and immunological abnormalities were seen in the triple mutant, IL-6(-/-)/gp130(F759/F759)/pX-Tg, indicating that the arthritis in the double mutant is IL-6 dependent. gp130(F759/F759)/pX-Tg is a unique mouse model for RA.
  • 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 0037-1017 2004/02 [Refereed][Not invited]
  • 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 0041-1337 2003/10 [Refereed][Not invited]
     
    Background We have previously demonstrated that blockade of either CD80/86-CD28 or CD40-CD154 costimulatory pathways by using adenovirus vector coding CTLA4Ig (AdCTLA4Ig) or CD40Ig (AdCD40Ig) genes induced donor-specific tolerance in rat liver transplantation. In this study, we asked whether these gene-therapy-based costimulation blockade would induce tolerance in cardiac transplantation. Methods. Heterotopic heart transplantation was performed in a full major histocompatibility complex (MHC) barrier combination of ACI (RT1(av1)) to Lewis (LEW, RT1(1)) rats. Vector (1x10(9) plaque forming unit [PFU]), AdLacZ, AdCTLA4Ig, or AdCD40Ig, was administered intravenously to recipient animals immediately after grafting, and graft survival, serum CTIA4Ig/CD40Ig levels, and graft histology were assessed. Tolerance was determined by secondary skin-graft challenging. Results. Allografts of both untreated and AdLacZ controls were promptly rejected within 7 days, whereas a single treatment with AdCTLA4Ig or AdCD40Ig significantly prolonged median graft survival to 55.5 and 28.5 days, respectively. In contrast, the combined AdCTLA4Ig and AdCD40Ig gene therapy maintained high CTLA4Ig and CD40Ig levels through the posttransplant period and allowed long-term cardiac allograft survival for more than 270 days. However, both donor and third-party skin grafts were rejected in the animals who harbored cardiac grafts over 150 days. Also, typical features of chronic rejection were evident in the long-term surviving grafts. Conclusion. Simultaneous blockade of CD28 and CD154 path-ways by AdCTLA4Ig plus AdCD40Ig induces a strong immunosuppression that allows long-term acceptance of full MHC mismatched cardiac graft in rats. This:; strategy, however, was not enough to induce tolerance to skin grafts and to avoid chronic rejection, as shown in the liver-transplantation model.
  • 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 1529-2908 2003/06 [Refereed][Not invited]
     
    Whereas interleukin-6 (IL-6) is a proinflammatory cytokine, IL-10 is an anti-inflammatory cytokine. Although signal transducer and activator of transcription 3 (STAT3) is essential for the function of both IL-6 and IL-10, it is unclear how these two cytokines have such opposing functions. Here we show that suppressor of cytokine signaling 3 (SOCS3) is a key regulator of the divergent action of these two cytokines. In macrophages lacking the Socs3 gene or carrying a mutation of the SOCS3-binding site in gp130, the lipopolysaccharide-induced production of tumor necrosis factor (TNF) and IL-12 is suppressed by both IL-10 and IL-6. SOCS3 specifically prevents activation of STAT3 by IL-6 but not IL-10. Taken together, these data indicate that SOCS3 selectively blocks signaling by IL-6, thereby preventing its ability to inhibit LPS signaling.
  • 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 0953-8178 2003/06 [Refereed][Not invited]
     
    Transcriptional expression of a gene or genes is absolutely required for induction of glucocorticold-induced thymocyte apoptosis. We have previously shown that expression of T cell death-associated gene 8 (TDAG8) is quickly induced exclusively in the thymus after dexamethasone (DEX) treatment. Here, we present data that TDAG8 expression is induced prior to induction of DEX-mediated apoptosis. In contrast, TDAG8 expression in thymocytes was not induced in the process of gamma-irradiation-mediated apoptosis. TDAG8 expression accelerated only DEX-induced, but not TCR-mediated or gamma-irradiation-induced, thymocyte apoptosis in transgenic mice overexpressing TDAG8. Interestingly, these effects were specifically detected in CD4(+)CD8(+) double-positive thymocytes. Moreover, activation of caspase-3, -8 and -9 was enhanced in thymocytes of TDAG8 transgenic mice after DEX stimulation. In conclusion, TDAG8 expression is involved in glucocorticold-induced signals to activate caspase-9, -8 and -3 for subsequent apoptosis induction in CD4(+)CD8(+) double-positive thymocytes.
  • 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 0041-1337 2003/02 [Refereed][Not invited]
     
    Background. The blockade of costimulatory signal pathway by anti-CD40 ligand antibody or cytotoxic T lymphocyte antigen 4 immunoglobulin (CTLA4Ig) prolongs allograft survival in various vascularized organ transplantations. Because of the short half life of these agents, repeated administration of proteins is required to achieve significant graft survival. Furthermore, there is limited information regarding the effect of cosimulatory blockade on the survival of composite tissue allografts. Therefore, we examined the effect of adenovirus-mediated gene transfer of CTLA4Ig or CD40Ig gene or both in composite tissue allotransplantation. Methods. The hind limbs removed from male ACI rats (RT1(a)) were transplanted into female Lewis rats (RT1(1)) heterotopically. The recombinant adenovirus carrying CTI.A4Ig (AxCTLA4Ig) or CD40Ig (AxCD40Ig) was intravenously administered after limb transplantation. Results. Limb allograft survival was significantly prolonged by either AxCTLA4Ig or AxCD40Ig treatment at 1 x 10(9) plaque forming unit (mean survival time [MST] of 39.4 +/- 6.0 and 13.0 +/- 2.9, respectively) compared with the adenovirus vector containing beta-galactosidase-treated group (MST of 4.8 +/- 0.8). Combination of AxCTLA4Ig and AxCD40Ig led to significant prolongation of graft survival (MST of 49.2 +/- 6.6). Serum levels of CD40Ig were higher in rats treated with combination therapy than those treated with AxCD40Ig alone, whereas the serum levels of CTLA4Ig in rats treated with AxCTLA4Ig alone and AxCTLA4Ig and AxCD40Ig combined were very similar. Conclusion. This study indicates that an adenovirus-mediated gene therapy of CTLA4Ig or CD40Ig has a therapeutic potential for preventing rejection in composite tissue transplantation. Furthermore, a combination therapy of AxCTLA4Ig and AxCD40Ig was even more effective in preventing acute rejection and prolonging the survival of allografted limbs without apparent complication.
  • [Role of cytokines for maintenance of memory CD8+ T cells].
    Kamon H, Murakami M
    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 16 Suppl 47 2313 - 2317 0039-9450 2002/12 [Refereed][Not invited]
  • BJ Swanson, M Murakami, TC Mitchell, J Kappler, P Marrack
    IMMUNITY 17 (5) 605 - 615 1074-7613 2002/11 [Refereed][Not invited]
     
    An examination of differences in gene expression between memory and naive phenotype T cells revealed elevated levels of mRNA for several chemokines, especially RANTES, in memory phenotype T cells. Although RANTES mRNA is spliced and cytoplasmic, these cells do not contain or secrete significant amounts of RANTES protein without TCR stimulation. This secretion is independent of transcription, but requires translation. In vivo, CD8+ memory T cells proliferate continuously and slowly in response to IL-15; however, IL-15 does not stimulate RANTES secretion. These results show that memory phenotype CD8+ T cells use preexisting mRNA to produce and secrete RANTES rapidly following TCR stimulation. Such storage of preformed mRNAs for important inflammatory mediators may contribute to the speed of secondary immune responses.
  • 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 0250-7005 2002/11 [Refereed][Not invited]
     
    Background: B7 family members play a central costimulatory role in T cell activation. We identified B7-1alpha, an alternatively spliced form of B7-1. The therapeutic efficacy of B7-1alpha-expressing tumor vaccine remains uncertain. Materials and Methods: The murine osteosarcoma cell line, LM8, was engineered to express equivalent levels of B7-1 (B7-1-LM8) and B7-1alpha (B7-1alpha-LM8). The therapeutic efficacy of B7-transfected cells and anti-CTLA-4 blocking mAb was evaluated by the mixing experiments on the primary tumor, pulmonary metastasis and survival time. Results: (i) a mixture of B7-1-LM8 or B7-1alpha-LM8 cells inhibited growth of the subcutaneous LM8 tumors and augmented the therapeutic effects of anti-CTLA-4 mAb and (ii) a combination of B7-1alpha-LM8 cells and anti-CTLA-4 mAb most significantly eradicated pulmonary metastasis and prolonged the survival time of mice. Conclusion: These findings suggest that intrinsic (lack of IgC-like domain in B7-1alpha) and extrinsic (anti-CTLA-4 mAb) manipulations of B7/CTLA-4 interaction synergistically improve the therapeutic efficacy of B7-based osteosarcoma vaccines.
  • 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 0250-7005 2002/07 [Refereed][Not invited]
     
    Background: B7 family members play a central costimulatory role in T cell activation. We have previously identified B7-1a, an. alternatively spliced form of B7-1. The function of B7-1a in induction of anti-tumor immunity remains uncertain. Materials and Methods: The cDNAs of murine B7-1, B7-1a and B7-2 were introduced into a murine osteosarcoma cell line, LM8. The ability of B7 transfectants to elicit in vivo anti-tumor immunity was comparatively analyzed with respect to tumorigenecity, pulmonary metastasis and survival time. Results: LMS cells expressing B7-1, B7-1a, or B7-2 all elicited immunological responses in immunocompetent C3H/He mice. Notably, the anti-tumor effects were most obvious in mice inoculated with B7-1a-transfected LM8 cells. Such a difference among B7-transfectants became indistinguishable in immunodeficient nude mice. Conclusion: These findings indicate that B7-1a serves as a more efficacious costimulatory molecule than B7-1 or B7-2 in the induction and maintenance of anti-tumor immune responses against a poorly immunogenic osteosarcoma cell line.
  • 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 0020-7136 2002/07 [Refereed][Not invited]
     
    Expression of the Wilms' tumor gene WTI in de novo lung cancer was examined using quantitative real-time RT-PCR and immunohistochemistry. Overexpression of the WTI gene was detected by RT-PCR in 54/56 (96%) de novo non-small cell lung cancers examined and confirmed by detection of WTI protein with an anti-WTI antibody. Overexpression of the WTI gene was also demonstrated in 516 (83%) de novo small cell lung cancers by immunohistochemistry. Furthermore, when the WTI gene was examined for mutations by direct sequencing of genomic DNA in 7 lung cancers, no mutations were found. These results suggest that the non-mutated, wild-type WTI gene plays an important role in tumorigenesis of de novo lung cancers and may provide us with the rationale for new therapeutic strategies for lung cancer targeting the WTI gene and its products. (C) 2002 Wiley-Liss, Inc.
  • K Konishi, M Inobe, A Yamada, M Murakami, S Todo, T Uede
    JOURNAL OF HEART AND LUNG TRANSPLANTATION 21 (6) 692 - 700 1053-2498 2002/06 [Refereed][Not invited]
     
    Background: Mouse heterotopic tracheal transplantation offers a reproducible model of obliterative bronchiolitis after lung transplantation. CTLA4IgG inhibits signaling of the CD28/B7 pathway and induces antigen-specific T-cell unresponsiveness. FTY720 induces T-cell apoptosis and sequestration of circulating mature lymphocytes. We previously found that CTLA4IgG could prevent the development of obliterative airway disease but could not preserve the respiratory epithelium of grafted tracheae. We evaluated whether treatment with either FTY720 or CTLA4IgG, or with combination FTY720 and CTLA4IgG could preserve the respiratory epithelium and inhibit the development of obliterative airway disease. Methods: Tracheae with main bronchi from C3H/He mice were transplanted heterotopically into BALB/C mice and harvested on Day 35. Recipient mice received either no treatment or treatment with intraperitoneal FTY720, CTLA4IgG, or the combination of the 2. Results: Either FTY720 or CTLA4IgG alone significantly inhibited the development of obliterative airway disease. However, normal ciliated columnar respiratory epithelial cells were lost in the allografts. In contrast, combination therapy preserved the respiratory epithelium of the allografted tracheae. FTY720 concentration in the tissue was very high; treatment with FTY720 inhibited mixed lymphocyte reactions and augmented T-cell apoptosis. Conclusion: Combination treatment with FTY720 and CTLA4IgG may prevent obliterative airway disease.
  • 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 0027-8424 2002/06 [Refereed][Not invited]
     
    Previously we demonstrated that IL-15 and IL-2 control the number of memory CD8+ T cells in mice. IL-15 induces, and IL-2 suppresses the division of these cells. Here we show that CD25+CD4+ regulatory T cells play an important role in the IL-2-mediated control of memory phenotype CD8+ T cell number. in animals, the numbers of CD25+CD4+ T cells were inversely correlated with the numbers of memory phenotype CD8+ T cells with age. Treatment with anti-IL-2 caused CD25+CD4+ T cells to disappear and, concurrently, increased the numbers of memory phenotype CD8+ T cells. This increase in the numbers of CD8+ memory phenotype T cells was not manifest in animals lacking CD4+ cells. Importantly, adoptive transfer of CD25+CD4+ T cells significantly reduced division of memory phenotype CD8+ T cells. Thus, we conclude that CD25+CD4+ T cells are involved in the IL-2-mediated inhibition of memory CD8+ T cell division and that IL-2 controls memory phenotype CD8+ T cell numbers at least in part through maintenance of the CD25+CD4+ T cell population.
  • 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 0041-1337 2002/05 [Refereed][Not invited]
     
    Background. Blockade of CD40-CD40 ligand (CD154) costimulatory pathway with anti-CD154 antibody (Ab) prolongs allograft survival in experimental organ transplantations; however, repeated agent administration is needed to provide an adequate immunosuppression. Seeking for simple and effective approach to interfere this signaling, we applied adenovirus-mediated gene therapy by encoding CD40Ig gene (AdCD40Ig). Methods. Liver graft from ACI (RT1(av1)) rat was transplanted orthotopically into LEW (RT1(1)) rat, and AdCD40Ig was given to animals via the penile vein immediately after grafting (n=6). Results. A single treatment with AdCD40Ig at 1 x 10(9) plaque forming units induced specific expression of CD40Ig gene on allograft liver, produced substantial amount of the protein in the sera, and allowed indefinite graft survival. Whereas, LEW recipients given no treatment or control adenovirus vector (AdLacZ) promptly rejected ACI liver. In addition, AdCD40Ig-treated, long-term survivors accepted skin graft from the donor strain but not the third party graft. Histopathology revealed that liver structure of the long-term surviving animals was completely preserved in normal with no infiltration of mononuclear cells. Conclusion. Blockade of CD40-CD154 pathway by CD40Ig gene therapy is a potent alloantigen-specific immunosuppressive strategy to induce permanent acceptance of liver allograft and would be a new therapeutic candidate in a clinical liver transplantation.
  • 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 0910-8327 2002/03 [Refereed][Not invited]
     
    Osteopontin (OPN), a noncollagenous adhesive protein, may possibly be implicated in atherosclerosis, in which macrophages and activated T lymphocytes could have higher OPN levels within the atherosclerotic plaques. However, it is not known whether a higher OPN level is a cause or a result of atherosclerosis or whether it has a promoting or inhibitory effect on atherosclerosis, To clarify the role of OPN in atherosclerosis, we developed a transgenic mouse (OPN-TG) in which the exogenous OPN gene was designed to be expressed by hematopoietic cells, expressing OPN, which carried the immunoglobulin enhancer (Emu)/SV40 promoter. In OPN-TG, the expression of exogenously transfected OPN RNA was found in lymphoid organs, such as the thymus and spleen, and the kidney. In the present study, OPN-TG mice were assigned into two groups, an atherogenic diet group (15% fat, 1.25% cholesterol) for 3 months or a standard diet group (4% fat), and both groups were compared with wild-type C57BL/6 mice to investigate the relationship between osteopontin and the atherosclerotic lesion. In wild-type mice, OPN mRNA was detected in kidney, but not in lymphoid tissues. In both OPN-TG and wild-type mice fed with control diets, atherosclerotic lesions were not found in the aortic sinus or the thoracic and abdominal aorta. In both OPN-TG and wildtype mice fed with atherogenic diets, a high incidence of atherosclerotic lesions was noted in the aortic sinus. The atherosclerotic lesions were significantly larger in OPN-TG as compared with those in control littermate mice (size: 33.8% +/- 23.4% vs 10.9% +/- 20.4%, respectively, P < 0.05). Activated foamy macrophages within atherosclerotic plaque in OPN-TG expressed a considerably larger amount of OPN compared with such macrophages in control mice. The OPN protein detected in the atherosclerotic lesions was not due to the deposition of serum OPN., but mainly due to in situ production by the infiltrating macrophages. Thus, these results suggest that OPN is atherogenic and that macrophages expressing OPN can be easily activated and thus promote atheromatous lesions if a high fat diet is consumed.
  • 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 0041-1337 2002/02 [Refereed][Not invited]
     
    Background. Although recent experimental studies have demonstrated CTLA4Ig to be a potent immunosuppressant in vascularized solid organ allografts, little attention has been given to the effect of this soluble recombinant fusion protein on immunosuppression in composite tissue allografts (CTAs). Using a rat hind limb allograft model, we examined the efficacy of CTLA4Ig against the allograft rejection of composite tissue. Methods. The hind limbs of ACI rats (RT1(a)) were heterotopically transplanted to Lewis rats (RT1(1)). Controls received no immunotherapy. Experimental recipients were treated with a single i.p. injection of either human immunoglobulin (Ig)G (0.5 mg/body) or CTLA4Ig (0.5 mg/body) according to different time schedules. Graft survival time and histopathological changes for each experimental group were evaluated and statistically compared. Results. Graft survival times were prolonged significantly in rats treated with CTLA4Ig on day 1 and day 2 after transplantation, compared with survival times of controls. In particular, the most significant prolongation was found in rats treated on day 2. At 7 days after transplantation, moderate-to-severe histological rejection occurred in all tissues in control rats. On the other hand, in rats treated with CTLA4Ig, all tissues showed significantly better preservation. Among these treated rats, the rats treated on day 2 showed excellent histopathological conditions in each tissue. Conclusions. This study supports the feasibility of using CTLA4Ig for preventing acute rejection in CTA. On the basis of the current results, the administration of CTLA4Ig for CTA is more effective at 24-48 hr after transplantation, after the initial immune response has been allowed to begin.
  • H Ueno, F Nakamura, M Murakami, M Okumura, T Kadosawa, T Fujinaga
    BIOMATERIALS 22 (15) 2125 - 2130 0142-9612 2001/08 [Refereed][Not invited]
     
    Chitosan is reported as an accelerator of wound healing. Histological findings of previous reports indicate that chitosan accelerates the reformation of connective tissue, however the details of the mechanism are not clear. In this study, firstly L929 mouse fibroblasts were cultured with chitosan and the production of extracellular matrix (ECM) was evaluated in vitro. Type I and III collagens and fibronectin were secreted by L929 with or without chitosan; however there was no significant difference in the amount of ECM between the control and the chitosan groups. Secondly, macrophages were stimulated with chitosan, and then transforming growth factor-beta 1 (TGF-beta1) and platelet-derived growth factor (PDGF) messenger ribonucleic acid (mRNA) expressions and production of their proteins were assayed in vitro. As a result, chitosan promoted the production of TGF-beta1 and PDGF. These results indicate that chitosan does not directly accelerate ECM production by fibroblast and the ECM production may increase by the growth factors. (C) 2001 Elsevier Science Ltd. All rights reserved.
  • 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 1043-0342 2001/06 [Refereed][Not invited]
     
    We previously constructed an adenovirus vector carrying a gene encoding a soluble form of fusion protein, consisting of the extracellular portion of cytotoxic lymphocyte antigen 4 (CTLA4) and the Fc portion of human immunoglobulin G1 (Adex1CACTLA4IgG). Murine type II collagen-induced arthritis (CIA) was treated with Adex1CACTLA4IgG. A single intraarticular injection of 1 x 10(5) PFU was able to support serum CTLA4IgG at more than 10 mug/ml for at least 12 weeks and was able to inhibit the CIA clinically and histologically. In contrast, intravenous, intramuscular, or subcutaneous injection of 1 x 10(5) PFU was unable to support a significant level of serum CTLA4IgG and thus was unable to inhibit the development of arthritis. Thus, we demonstrated that (1) a low-dose intraarticular injection of Adex1CACTLA4IgG was effective in delaying the onset of CIA and reducing the severity of arthritis; (2) an intraarticular (knee joint) injection of Adex1CACTLA4IgG effectively blocked the development of arthritis in distal paws; (3) the inhibitory effect of Adex1CACTLA4IgG lasted at least up to 20 weeks; (4) although serum CTLA4IgG at more than 10 mug/ml persisted for at least 12 weeks, mice treated by intraarticular injection of Adex1CACTLA4IgG were not anergic to adenovirus and were able to mount antibody responses against various antigens.
  • H Ueno, M Murakami, M Okumura, T Kadosawa, T Uede, T Fujinaga
    BIOMATERIALS 22 (12) 1667 - 1673 0142-9612 2001/06 [Refereed][Not invited]
     
    Chitosan is a copolymer of beta (1 --> 4) glucosamine and N-acetyl-D-glucosamine, which accelerates the infiltration of polymorphonuclear leukocytes (PMN) in the early phase of wound healing. In the granulation tissue treated with chitosan in canine experimental wound, osteopontin (OPN) was strongly positive in PMN immunohistochemically. OPN is a glycosylated phosphoprotein and promotes the attachment or spread of a variety of cell types. In addition, OPN may play a role in granulomatous inflammation. Production of OPN in PMN was therefore investigated in vitro using human PMN in this study. PMN stimulated with granulocyte-colony stimulating factor (G-CSF) and chitosan accumulated OPN mRNA, and released OPN into their culture supernatants. These findings suggest that OPN is synthesized by migrating PMN which plays the novel role of regulating the evolution of wound healing with chitosan treatment at the early phase of healing, (C) 2001 Elsevier Science Ltd. All rights reserved.
  • 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 1043-0342 2001/03 [Refereed][Not invited]
     
    CTLA4IgG was shown to inhibit the costimulatory signal for T cell activation by interfering with the ligation of CD28 and B7-1 or B7-2. To inhibit various immune responses including acute cellular rejection of allografts, a certain level of serum CTLA4IgG should be maintained for an appropriate period. We previously reported on an adenovirus vector containing CTLA4IgG, which we designated Adex1CACTLA4IgG. Adex1CACTLA4IgG was able to maintain a significant level of serum CTLA4IgG for a long period on intravenous injection, which in turn inhibited various immune responses including protective immunity against infectious agents. To overcome the inhibitory effect, we constructed a new adenovirus vector, Adex1CALoxCTLA4IgGLox, by cloning CTLA4IgG cDNA between two loxP sequences under the control of the CAG promoter. We demonstrated that the administration of adenovirus vector containing Cre recombinase gene (Adex1CACre) at the desired time induced Cre-mediated recombination within a gene derived from Adex1CALoxCTLA4IgGLox vector, and the cDNA of CTLA4IgG was excised from the transduced gene and terminated the expression of CTLA4IgG in vitro and in vivo. More importantly, we also demonstrated that the long-term acceptance of allografts was achieved after the termination of CTLA4IgG expression, while the immune response against adenovirus was restored.
  • 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 0041-1345 2001/02 [Refereed][Not invited]
  • 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 0385-5600 2000 [Refereed][Not invited]
     
    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.
  • 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 0008-5472 1999/01 [Not refereed][Not invited]
     
    The expression of osteopontin (OPN), CD44 variants, and integrins has been correlated with tumorigenesis and metastasis. Here we show that these proteins cooperate to enhance cell motility, First, we demonstrate that several different CD44 variants bind to OPN in an arginine-glycine-aspartic acid-independent manner, but that the standard form of CD44 does not. These CD44 variants bind to both the amino- and COOH-terminal portions of OPN independently of the arginine-glycine-aspartic acid sequence, suggesting that multiple domains on OPN can be bound by the CD44 variants, Antibodies directed against the integrin beta 1 subunit are able to inhibit this binding. The binding of CD44 variants to OPN is significantly augmented by both anti-CD44s and anti-CD44v antibodies, This augmentation by anti-CD44 antibodies is OPN specific and, again, can be blocked by anti-beta 1 antibodies. Finally, we show that OPN binding by CD44 variants/beta 1-containing integrins promotes cell spreading, motility, and chemotactic behavior.
  • 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 0262-0898 1998/03 [Refereed][Not invited]
     
    We have previously shown that expression of costimulatory ligand B7-1 on MHC class I+ tumor cells (B16-BL6 melanoma) resulted in marked reduction of lung metastasis caused by i.v. injection into immunocompetent syngeneic mice and led to induction of immunity to the challenge by the parental B7-1 negative tumor. Here we investigated the effectiveness of irradiated B7-1 transfected tumor cells as a vaccine on established tumor metastasis and whether or not expression of B7-1 molecule on tumor cells in combination with administration of anti-adhesion peptide FC-336 can augment the antimetastatic efficacy. Immunization with X-irradiated B7-1 transfectants after i.v. injection of B7-1(-) parental B16-BL6 cells was effective in inhibiting lung metastasis. We also found that vaccination with irradiated B7-1 transfectants after excision of primary tumor on day 21 resulted in significant inhibition of spontaneous lung metastasis by intrafootpad injection of viable parental B16-BL6 melanoma, as compared with the untreated control. However, immunizing twice with mock transfectants did not affect inhibition of spontaneous lung metastasis of wild-type tumors. On the other hand, multiple administration of a pseudo-peptide of RGD sequence (FC-336) after tumor inoculation inhibited spontaneous lung metastasis through the interference of tumor invasion, migration and adhesion. Combined treatment of B7-1 transfected tumor vaccine and anti-adhesive therapy with FC-336 led to the augmentation of the antimetastatic effect in both experimental and spontaneous metastasis models, as compared with either treatment alone. B7-1- and FC-336-mediated inhibition of tumor metastasis may be mediated by different mechanisms at various steps of metastasis, based on the regulation (promotion or inhibition) of tumor interaction with host cells and components. (C) 1998 Rapid Science Ltd.
  • 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 0385-5600 1998 [Refereed][Not invited]
     
    To evaluate the role of B7 on thymocyte activation and apoptosis, we took advantage of TCR transgenic mice in which the majority of thymocytes express a uniform TCR that is specific for ovalbumin, We also prepared Chinese hamster ovary (CHO) cells expressing B7 and appropriate class II molecules. We found that the apoptosis of double-positive thymocytes by TCR-mediated signaling, which presumably represents negative selection, requires a costimulatory signal provided by B7-1 or B7-2. The requirement of B7-1 costimulation for the apoptosis of thymocytes does not change in either low or high antigenic peptide loading. We also demonstrated that two signals through TCR and CD28 augmented the proliferation of thymocytes, and the requirement of CD28-mediated signal by B7-1 or B7-2 for thymocyte proliferation became less evident when high doses of antigenic peptide were loaded, indicating that the intensity of TCR-mediated signal determines the requirement of B7-mediated second signal for thymocyte proliferation.
  • 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 0027-8424 1996/07 [Refereed][Not invited]
     
    To determine whether alternative cytotoxic T lymphocyte-associated protein 4 (CTLA4) binding proteins exist on B cells, we constructed (i) mCTLA4hIgG consisting of the extracellular region of a mouse CTLA4 molecule and the Fc portion of a human IgG1 molecule and (ii) PYAAhIgG, a mutant mCTLA4hIgG, having two amino acid substitutions on the conserved MYPPPY motif in the complementarity-determining region 3-like region and lacking detectable binding to both B7-1 and B7-2 molecules. Using these fusion proteins (mCTLA4hIgG and PYAAhIgG), we demonstrated that a mouse immature B-cell line, WEH1231 cells, expressed alternative CTLA4 binding molecules (ACBMs) that were distinct from both B7-1 and B7-2. ACBMs were 130-kDa disulfide-linked proteins. More importantly, ACBMs were able to provide costimulatory signal for T-cell proliferation in the presence of anti-CD3 monoclonal antibodies. In addition, we demonstrated that more than 20% of B220(+) cells obtained from normal mouse spleen expressed ACBMs.
  • 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 0020-7136 1996/04 [Refereed][Not invited]
     
    The present study demonstrates that the transfection of B7-1 or its variant MB7-2 genes into MHC class 1(+) tumor cells (B16-BL6 or K1735-M2 melanoma) resulted in the remarkable reduction of lung metastasis caused by i.v. injection into immunocompetent syngeneic mice. However, i.v. injection of the transfectants into T cell-deficient nude mice did not affect reduction of lung tumor colonies as compared with parental wild-type tumors, suggesting that such an inhibitory effect was closely associated with T cell-mediated responses. The reduced metastasis of B7(+) tumor cells consequently led to the significant prolongation of survival. Expression of B7 on tumor cells did not influence the tumorigenicity in vivo and tumor cell invasion into basement membrane Matrigel in vitro. We also found that immunization of X-irradiated by transfectants was effective as a tumor vaccine for preventing lung metastasis caused by i.v. injection of B7(-) parental B16-BL6 cells but not against other syngeneic 3LL tumors. Thus, the by-mediated anti-metastatic effect was tumor-specific. Vaccinations of irradiated B7(+) tumor cells before and after surgical excision of the s.c. inoculated primary B7(-) tumors on day 21 achieved effectively the prevention of spontaneous lung metastasis. Our report that vaccination of irradiated B7(+) tumor cells led to a therapeutic effect in an established tumor metastasis model clearly expands and confirms previous related observations. (C) 1996 Wiley-Liss, Inc.
  • A Yamada, M Murakami, K Ijima, H Yagita, K Okumura, S Komatsu, T Uede
    MICROBIOLOGY AND IMMUNOLOGY 40 (7) 513 - 518 0385-5600 1996 [Not refereed][Not invited]
     
    The immunosuppressant FK506 prolongs allograft survival. However, at therapeutic doses it has significant side effects. A fusion protein consisting of the extracellular portion of CTLA4 and the Fe portion of human IgG (CTLA4IgG) also prolongs allograft survival, but large doses of CTLA4IgG are required for the induction of cardiac allograft acceptance. Therefore, we constructed a pentameric form of a new CTLA4 fusion protein, CTLA4IgM. We tested whether low doses of CTLA4IgG or CTLA4IgM in combination with subtherapeutic doses of FK506 can prolong allograft survival in a synergistic fashion. C57BL/6 (H-2(b)) neonatal hearts were transplanted to CBA/J (H-2(k)) mice in a heterotopic, nonvascularized cardiac allograft model. The findings demonstrate that a combination of low doses of FK506 plus a pentameric form of CTLA4Ig, CTLA4IgM, leads to significant graft survival, while a combination of FK506 plus CTLA4IgG does not.
  • IL-6 AND IL-6 RECEPTOR
    M MURAKAMI, T HIRANO
    SEIKAGAKU 62 (1) 32 - 35 0037-1017 1990/01 [Refereed][Not invited]
  • 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, 水野信哉, 大友勘十郎
    日本獣医師会誌 42 491 - 494 1989 [Refereed][Not invited]

Conference Activities & Talks

  • 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  [Invited]
    村上 正晃
    第13回神経-筋の免疫疾患を考える会  2013
  • EAE investigation by using the ultra-high field MRI.  [Invited]
    Masaaki Murakami
    Osaka University Live Immuno-Imaging Facility Opening workshop  2013
  • Masaaki Murakami
    34th International Society for Gravitational Physiology  2013
  • 炎症アンプによる病気、病態の制御  [Invited]
    村上 正晃
    次世代重点研究プログラムセミナー  2013
  • 炎症の慢性化機構の解明と制御  [Invited]
    村上 正晃
    第18回日本病態プロテアーゼ学会学術集会  2013
  • 慢性炎症の誘導機構”炎症アンプ”の活性化と病態形成  [Invited]
    村上 正晃
    第6回Symphony  2013
  • 炎症アンプの活性化と関節炎の発症  [Invited]
    村上 正晃
    小児リウマチ学会  2013
  • 炎症の慢性化誘導機構『IL-6アンプ』と関節炎  [Invited]
    村上 正晃
    第56回日本リウマチ学会学術集会  2012
  • 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  [Invited]
    村上 正晃
    第46回北摂循環器研究会  2012
  • 非免疫細胞に存在する炎症誘導機構、 IL-6アンプ  [Invited]
    村上 正晃
    北海道大学遺伝子病制御研究所セミナー  2012
  • 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  [Invited]
    村上 正晃
    第22回サイトメトリー学会学術集会  2012
  • 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  [Invited]
    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
  • 局所の神経活性化による自己免疫病の制御  [Invited]
    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
  • IL-6アンプと慢性炎症  [Invited]
    村上 正晃
    第27回日本整形外科学会基礎学術集会  2012
  • 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—  [Invited]
    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
  • 重力刺激による中枢神経系への免疫細胞侵入口の形成  [Invited]
    村上 正晃
    第58回日本宇宙航空環境医学会  2012
  • 活性化T細胞と中枢神経系の病気、病態  [Invited]
    村上 正晃
    第41回日本免疫学会学術集会  2012
  • Local neural pathway and a gateway for pathogenic T cells in the CNS  [Invited]
    Masaaki Murakami
    2012 Annual Meeting of the Japanese Society for Immunology  2012
  • Regional neural activation defines a gateway in the blood brain barrier for immune cells  [Invited]
    Masaaki Murakami
    IFReC-SIgN Winter School  2012
  • サイトカインと慢性炎症—“IL-6アンプ”の役割  [Invited]
    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
  • 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  [Invited]
    村上 正晃
    第12回東北大学がん・エピゲノム研究会  2012
  • 中枢神経系への免疫細胞の侵入メカニズム  [Invited]
    村上 正晃
    第40回日本臨床免疫学会総会・シンポジウム  2012
  • 免疫細胞の中枢神経系への侵入口と仕組みについて  [Invited]
    村上 正晃
    第17回グリア研究会・招待セミナー  2012
  • IL-17A-triggered positive-feedback for IL-6-signaling, a key player for inflammation, is associated with various human diseases.  [Invited]
    Masaaki Murakami
    RCAI-CGM Joint Meeting  2011
  • Inflammation and Zinc signaling.  [Invited]
    Masaaki Murakami
    The 5th International Conference on Metals and Genetics  2011
  • The IL-6 amplifier activation, a key player of inflammation, in human diseases and disorders.  [Invited]
    Masaaki Murakami
    Annual Meeting of the Japanese Society for Immunology・International symposium  2011
  • Masaaki Murakami
    The 60th Fujihara Seminar Zinc Signaling and Cellular Functions  2010
  • How does IL-17 induce Autoimmune Diseases?  [Invited]
    Masaaki Murakami
    The 2nd International Symposium of WPI-IFReC  2009
  • Liver as a regulator of T cells.  [Invited]
    Masaaki Murakami
    The 5th International Workshop of Kyoto T Cell Conference 2009  2009
  • Is the recognition of cognate antigens always required for the determination of the tissue specificity of autoimmune diseases associated with MHC II?”  [Invited]
    Masaaki Murakami
    Annual Meeting of the Japanese Society for Immunology  2009
  • 抗原提示におけるサイトカインとカテプシンの関係  [Invited]
    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
  • Foxp3+抑制性CD8+ T細胞による免疫反応の制御  [Invited]
    村上 正晃
    第18回日本サイトメトリー学会学術総会  2008
  • 細胞内亜鉛信号による細胞活性化の制御  [Not invited]
    村上 正晃
    日本薬学会第128回年会  2008
  • An IL-17-Triggered Positive Feedback Loop of IL-6 Signaling in Autoimmune Diseases.  [Invited]
    Masaaki Murakami
    Annual Meeting of the Japanese Society for Immunology  2008
  • Hepatic IL-7 controls T cell responses.  [Invited]
    Masaaki Murakami
    WPI-IFReC Third Seminar  2008
  • サイトカイン発現ネットワークと自己免疫疾患  [Invited]
    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
  • 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  [Invited]
    村上 正晃
    かずさDNA研究所セミナー  2007
  • 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  [Invited]
    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
  • IL-17 derived from homeostatic proliferating memory/activated CD4+ T cells develops arthritis in F759 mice  [Invited]
    Masaaki Murakami
    Annual Meeting of the Japanese Society for Immunology  2007
  • 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  [Invited]
    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
  • Zinc signaling in dendritic cells  [Invited]
    Masaaki Murakami
    The 20th Naito Conference on Innate Immunity in Medicine and Biology  2007
  • 免疫分野における高速セルソーターの応用  [Invited]
    村上 正晃
    第37回日本免疫学会学術集会  2007
  • 免疫分野における高速セルソーターの応用例  [Invited]
    村上 正晃
    第36回日本免疫学会学術集会  2006
  • Non-hematopoietic cell populations play a role for IL-6-mediated enhancement of CD4+ T cell activation  [Invited]
    Masaaki Murakami
    Annual Meeting of the Japanese Society for Immunology  2006
  • 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  [Invited]
    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
  • 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  [Invited]
    村上 正晃
    第14回日本癌病態治療研究会  2005
  • Hyperactivation of gp130-Mediated STAT3 signaling induces rheumatoid arthritis like disease.  [Invited]
    Masaaki Murakami
    第8回上原記念生命科学財団  2005
  • 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  [Invited]
    村上 正晃
    第13回日本アポトーシス研究会学術集会  2004
  • Anti-IL-2-meidated effecter CD8+ T cell activation.  [Invited]
    Masaaki Murakami
    Annual Meeting of the Japanese Society for Immunology  2003
  • 生体内でのメモリーT細胞の維持機構  [Invited]
    村上 正晃
    東京大学医学部免疫学教室セミナー  2002
  • The role of CD25+CD4+ T cells in control of memory CD8+ T cells.  [Invited]
    Masaaki Murakami
    Annual Meeting of the Japanese Society for Immunology  2002
  • Homeostasis of memory T cells.  [Invited]
    Masaaki Murakami
    The 2001 AAI Advanced Course in Immunology  2001
  • The maintenance of memory T cells in vivo.  [Invited]
    Masaaki Murakami
    Annual Scientific Meeting of the Gerontological Society of America  2000

Works

  • 炎症ストローマの人為的コントロールによる難治性慢性炎症疾患群の制御
    2010
  • 急性期蛋白による自己免疫疾患・感染症の制御
    2010
  • 関節リウマチ関連遺伝子の探索とその機能解析
    2006

MISC

  • 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  2018/09  [Not refereed][Not invited]
  • 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  2018/08  [Not refereed][Not invited]
  • 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  2017/12  [Not refereed][Not invited]
  • 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  2017/12  [Not refereed][Not invited]
  • 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-  2017/10  [Not refereed][Not invited]
  • 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  2017/08  [Not refereed][Not invited]
  • 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  2017/04  [Not refereed][Not invited]
  • 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  2016/08  [Not refereed][Not invited]
  • 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  2014/10/24  [Refereed][Not invited]
     
    © 2014 TSI Press. This paper demonstrates the possibility of in vivo imaging for neuroimmunological assessments using ultra high-field magnetic resonance imaging (UHF-MRI). UHF-MRI provides a highly sensitive MR microimaging technique could be used to identify previously invisible pathologies and cellular dynamics in the central nervous system (CNS) of living animals. Our technique could reveal the mechanisms underlying the immune responses and cell dynamics during neuroinflammation, CNS diseases, and also in the normal state.
  • 有馬 康伸, 村上 正晃  医薬ジャーナル  49-  (2)  109  -116,11  2013/02  [Not refereed][Not invited]
  • 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  2011/11/07  [Not refereed][Not invited]
  • 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  2011/01  [Not refereed][Not invited]
     
    Cognate antigen recognition by CD4(+) T cells is thought to contribute to the tissue specificity of various autoimmune diseases, particularly those associated with class II MHC alleles. However, we show that localized class II MHC-dependent arthritis in F759 mice depends on local events that result in the accumulation of activated CD4(+) T cells in the absence of cognate antigen recognition. In this model, transfer of in vitro polarized Th17 cells combined with the induction of experimental microbleeding resulted in CCL20 production, the accumulation of T cells in the joints, and local production of IL-6. Disease induction required IL-17A production by transferred T cells, IL-6 and CCL20 expression, and STAT3 signaling in type I collagen-expressing cells. Our data suggest a model in which the development of autoimmune disease in F759 mice depends on four events: CD4(+) T cell activation regardless of antigen specificity, local events that induce T cell accumulation, enhanced sensitivity to T cell-derived cytokines in the tissue, and activation of IL-6 signaling in the tissue. This model provides a possible explanation for why tissue-specific antigens recognized by activated CD4(+) T cells have not been identified in many autoimmune diseases, especially those associated with class II MHC molecules.
  • 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  2011/01  [Not refereed][Not invited]
     
    Cognate antigen recognition by CD4(+) T cells is thought to contribute to the tissue specificity of various autoimmune diseases, particularly those associated with class II MHC alleles. However, we show that localized class II MHC-dependent arthritis in F759 mice depends on local events that result in the accumulation of activated CD4(+) T cells in the absence of cognate antigen recognition. In this model, transfer of in vitro polarized Th17 cells combined with the induction of experimental microbleeding resulted in CCL20 production, the accumulation of T cells in the joints, and local production of IL-6. Disease induction required IL-17A production by transferred T cells, IL-6 and CCL20 expression, and STAT3 signaling in type I collagen-expressing cells. Our data suggest a model in which the development of autoimmune disease in F759 mice depends on four events: CD4(+) T cell activation regardless of antigen specificity, local events that induce T cell accumulation, enhanced sensitivity to T cell-derived cytokines in the tissue, and activation of IL-6 signaling in the tissue. This model provides a possible explanation for why tissue-specific antigens recognized by activated CD4(+) T cells have not been identified in many autoimmune diseases, especially those associated with class II MHC molecules.
  • 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  2010/05  [Not refereed][Not invited]
     
    Zinc (Zn) is an essential trace metal required by many enzymes and transcription factors for their activity or the maintenance of their structure. Zn has a variety of effects in the immune responses and inflammation, although it has not been well known how Zn affects these reactions on the molecular basis. We here showed that Zn suppresses T(h)17-mediated autoimmune diseases at lest in part by inhibiting the development of T(h)17 cells via attenuating STAT3 activation. In mice injected with type II collagen to induce arthritis, Zn treatment inhibited T(h)17 cell development. IL-6-mediated activation of STAT3 and in vitro T(h)17 cell development were all suppressed by Zn. Importantly, Zn binding changed the alpha-helical secondary structure of STAT3, disrupting the association of STAT3 with JAK2 kinase and with a phospho-peptide that included a STAT3-binding motif from the IL-6 signal transducer gp130. Thus, we conclude that Zn suppresses STAT3 activation, which is a critical step for T(h)17 development.
  • 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  2010/05  [Not refereed][Not invited]
     
    Zinc (Zn) is an essential trace metal required by many enzymes and transcription factors for their activity or the maintenance of their structure. Zn has a variety of effects in the immune responses and inflammation, although it has not been well known how Zn affects these reactions on the molecular basis. We here showed that Zn suppresses T(h)17-mediated autoimmune diseases at lest in part by inhibiting the development of T(h)17 cells via attenuating STAT3 activation. In mice injected with type II collagen to induce arthritis, Zn treatment inhibited T(h)17 cell development. IL-6-mediated activation of STAT3 and in vitro T(h)17 cell development were all suppressed by Zn. Importantly, Zn binding changed the alpha-helical secondary structure of STAT3, disrupting the association of STAT3 with JAK2 kinase and with a phospho-peptide that included a STAT3-binding motif from the IL-6 signal transducer gp130. Thus, we conclude that Zn suppresses STAT3 activation, which is a critical step for T(h)17 development.
  • Takayuki Nakagawa, Mineko Tsuruoka, Hideki Ogura, Yuko Okuyama, Yasunobu Arima, Toshio Hirano, Masaaki Murakami  INTERNATIONAL IMMUNOLOGY  22-  (2)  129  -139  2010/02  [Not refereed][Not invited]
     
    Although recent studies have identified regulatory roles for Foxp3(+)CD8(+) T cells, the mechanisms that induce their development and underlie their functions in vivo have not been elucidated. Here, we show that IL-6 positively regulates the Foxp3(+)CD8(+) T-cell development and function. The Foxp3(+)CD8(+) T cells that differentiated in vitro in the presence of IL-6 suppressed autoimmune colitis and arthritis in vivo. Moreover, Foxp3(+)CD8(+) T cells that developed in vivo in the presence of enhanced IL-6 signaling suppressed the development of a spontaneous T(h)17 cell-mediated autoimmune arthritis. Thus, we concluded that Foxp3(+)CD8(+) T cells develop in response to IL-6 and regulate chronic inflammation in T(h)17 cell-mediated F759 autoimmune arthritis. These results suggested that Foxp3(+)CD8(+) T cells may develop in response to IL-6 under certain inflammatory conditions in vivo and may regulate some other chronic inflammation diseases.
  • Takayuki Nakagawa, Mineko Tsuruoka, Hideki Ogura, Yuko Okuyama, Yasunobu Arima, Toshio Hirano, Masaaki Murakami  INTERNATIONAL IMMUNOLOGY  22-  (2)  129  -139  2010/02  [Not refereed][Not invited]
     
    Although recent studies have identified regulatory roles for Foxp3(+)CD8(+) T cells, the mechanisms that induce their development and underlie their functions in vivo have not been elucidated. Here, we show that IL-6 positively regulates the Foxp3(+)CD8(+) T-cell development and function. The Foxp3(+)CD8(+) T cells that differentiated in vitro in the presence of IL-6 suppressed autoimmune colitis and arthritis in vivo. Moreover, Foxp3(+)CD8(+) T cells that developed in vivo in the presence of enhanced IL-6 signaling suppressed the development of a spontaneous T(h)17 cell-mediated autoimmune arthritis. Thus, we concluded that Foxp3(+)CD8(+) T cells develop in response to IL-6 and regulate chronic inflammation in T(h)17 cell-mediated F759 autoimmune arthritis. These results suggested that Foxp3(+)CD8(+) T cells may develop in response to IL-6 under certain inflammatory conditions in vivo and may regulate some other chronic inflammation diseases.
  • 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  [Not refereed][Not invited]
  • 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  [Not refereed][Not invited]
  • Physical and Biological Sciences  86(7); 717-730-  2010  [Not refereed][Not invited]
  • Zinc is an intracellular signaling molecule: early and late signal
    2010  [Not refereed][Not invited]
  • Zinc and Th17-mediated autoimmune diseases
    2010  [Not refereed][Not invited]
  • Regulation of T cell Activation via a Metal Transporter
    2010  [Not refereed][Not invited]
  • Zinc and its transporters: Their roles in intracellular signaling and diseases
    2010  [Not refereed][Not invited]
  • IL-6 plays roles not only for developing Th17 but also for inducing an IL-6 amplifier in autoimmue diseases.
    2010  [Not refereed][Not invited]
  • Hepatic IL-7, which is Induced by TLR–Type I IFN Signaling, Promotes T cell Responses.
    2010  [Not refereed][Not invited]
  • Physical and Biological Sciences  86(7); 717-730-  2010  [Not refereed][Not invited]
  • Combination of IL-2 plus anti-IL-2 mAbs reduces cancer metastasis through activation of NK cells.
    2010  [Not refereed][Not invited]
  • Zinc is an intracellular signaling molecule: early and late signal
    2010  [Not refereed][Not invited]
  • Regulation of T cell Activation via a Metal Transporter
    2010  [Not refereed][Not invited]
  • 話題 肝からのIL-7の産生とその意義
    臨床免疫・アレルギー科  2010  [Not refereed][Not invited]
  • Homeostatic proliferation of CD4+ T cells is involved in the pathogenesis of a mouse model of Omenn syndrome.
    2010  [Not refereed][Not invited]
  • Specific antigen recognition by CD4+ T cells is not required for a MHC class II-associated autoimmune arthritis.
    2010  [Not refereed][Not invited]
  • Zinc and CD4+ T cell-mediated autoimmune diseases
    2010  [Not refereed][Not invited]
  • 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  [Not refereed][Not invited]
  • Homeostatic proliferation of CD4+ T cells is involved in the pathogenesis of a mouse model of Omenn syndrome.
    2010  [Not refereed][Not invited]
  • IFN-γ from CD8+ T cells, which is regulated by IL-6 signal, is involved in superantigen-mediated CD4+ T cell death.
    2010  [Not refereed][Not invited]
  • Specific antigen recognition by CD4+ T cells is not required for a MHC class II-associated autoimmune arthritis.
    2010  [Not refereed][Not invited]
  • Zinc and CD4+ T cell-mediated autoimmune diseases
    2010  [Not refereed][Not invited]
  • 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  [Not refereed][Not invited]
  • Zinc-mediated STAT3 suppression is involved in inhibition of autoimmune disease development via regulating Th17 differentiation.
    2010  [Not refereed][Not invited]
  • Zinc and Th17-mediated autoimmune diseases
    2010  [Not refereed][Not invited]
  • 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  [Not refereed][Not invited]
  • 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  [Not refereed][Not invited]
  • IFN-γ from CD8+ T cells, which is regulated by IL-6 signal, is involved in superantigen-mediated CD4+ T cell death.
    2010  [Not refereed][Not invited]
  • Hepatic IL-7, which is Induced by TLR–Type I IFN Signaling, Promotes T cell Responses.
    2010  [Not refereed][Not invited]
  • Zinc-mediated STAT3 suppression is involved in inhibition of autoimmune disease development via regulating Th17 differentiation.
    2010  [Not refereed][Not invited]
  • Combination of IL-2 plus anti-IL-2 mAbs reduces cancer metastasis through activation of NK cells.
    2010  [Not refereed][Not invited]
  • IL-6 plays roles not only for developing Th17 but also for inducing an IL-6 amplifier in autoimmue diseases.
    2010  [Not refereed][Not invited]
  • Yukihisa Sawa, Yasunobu Arima, Hideki Ogura, Chika Kitabayashi, Jing-Jing Jiang, Toru Fukushima, Daisuke Kamimura, Toshio Hirano, Masaaki Murakami  IMMUNITY  30-  (3)  447  -457  2009/03  [Not refereed][Not invited]
     
    Systemic cytokine activity in response to Toll-like receptor (TLR) signaling induces the expression of various proteins in the liver after infections. Here we show that Interleukin-7 (IL-7), the production of which was thought to occur at a constant rate in vivo, was a hepatically expressed protein that directly controled T cell responses. Depletion of IL-7 expression in the liver abrogated several TLR-mediated T cell events, including enhanced CD4(+) T cell and CD8(+) T cell survival, augmented CD8(+) T cell cytotoxic activity, and the development of experimental autoimmune encephalitis, a Th17 cell-mediated autoimmune disease. Thus, T cell responses are regulated by hepatocyte-derived IL-7, which is expressed in response to TLR signaling in vivo. We suggested that TLR-induced IL-7 expression in the liver, which is an acute-phase response, may be a good diagnostic and therapeutic target for efficient vaccine developments and for conditions characterized by TLR-mediated T cell dysregulation, including autoimmune diseases.
  • Yukihisa Sawa, Yasunobu Arima, Hideki Ogura, Chika Kitabayashi, Jing-Jing Jiang, Toru Fukushima, Daisuke Kamimura, Toshio Hirano, Masaaki Murakami  IMMUNITY  30-  (3)  447  -457  2009/03  [Not refereed][Not invited]
     
    Systemic cytokine activity in response to Toll-like receptor (TLR) signaling induces the expression of various proteins in the liver after infections. Here we show that Interleukin-7 (IL-7), the production of which was thought to occur at a constant rate in vivo, was a hepatically expressed protein that directly controled T cell responses. Depletion of IL-7 expression in the liver abrogated several TLR-mediated T cell events, including enhanced CD4(+) T cell and CD8(+) T cell survival, augmented CD8(+) T cell cytotoxic activity, and the development of experimental autoimmune encephalitis, a Th17 cell-mediated autoimmune disease. Thus, T cell responses are regulated by hepatocyte-derived IL-7, which is expressed in response to TLR signaling in vivo. We suggested that TLR-induced IL-7 expression in the liver, which is an acute-phase response, may be a good diagnostic and therapeutic target for efficient vaccine developments and for conditions characterized by TLR-mediated T cell dysregulation, including autoimmune diseases.
  • Yukihisa Sawa, Yasunobu Arima, Hideki Ogura, Chika Kitabayashi, Jing-Jing Jiang, Toru Fukushima, Daisuke Kamimura, Toshio Hirano, Masaaki Murakami  IMMUNITY  30-  (3)  447  -457  2009/03  [Not refereed][Not invited]
     
    Systemic cytokine activity in response to Toll-like receptor (TLR) signaling induces the expression of various proteins in the liver after infections. Here we show that Interleukin-7 (IL-7), the production of which was thought to occur at a constant rate in vivo, was a hepatically expressed protein that directly controled T cell responses. Depletion of IL-7 expression in the liver abrogated several TLR-mediated T cell events, including enhanced CD4(+) T cell and CD8(+) T cell survival, augmented CD8(+) T cell cytotoxic activity, and the development of experimental autoimmune encephalitis, a Th17 cell-mediated autoimmune disease. Thus, T cell responses are regulated by hepatocyte-derived IL-7, which is expressed in response to TLR signaling in vivo. We suggested that TLR-induced IL-7 expression in the liver, which is an acute-phase response, may be a good diagnostic and therapeutic target for efficient vaccine developments and for conditions characterized by TLR-mediated T cell dysregulation, including autoimmune diseases.
  • Yukihisa Sawa, Yasunobu Arima, Hideki Ogura, Chika Kitabayashi, Jing-Jing Jiang, Toru Fukushima, Daisuke Kamimura, Toshio Hirano, Masaaki Murakami  IMMUNITY  30-  (3)  447  -457  2009/03  [Not refereed][Not invited]
     
    Systemic cytokine activity in response to Toll-like receptor (TLR) signaling induces the expression of various proteins in the liver after infections. Here we show that Interleukin-7 (IL-7), the production of which was thought to occur at a constant rate in vivo, was a hepatically expressed protein that directly controled T cell responses. Depletion of IL-7 expression in the liver abrogated several TLR-mediated T cell events, including enhanced CD4(+) T cell and CD8(+) T cell survival, augmented CD8(+) T cell cytotoxic activity, and the development of experimental autoimmune encephalitis, a Th17 cell-mediated autoimmune disease. Thus, T cell responses are regulated by hepatocyte-derived IL-7, which is expressed in response to TLR signaling in vivo. We suggested that TLR-induced IL-7 expression in the liver, which is an acute-phase response, may be a good diagnostic and therapeutic target for efficient vaccine developments and for conditions characterized by TLR-mediated T cell dysregulation, including autoimmune diseases.
  • The recognition of specific antigens is not always required for the development of tissue-specific autoimmune diseases associated with MHC II.
    2009  [Not refereed][Not invited]
  • Impaired STAT activations in an ENU mutant mouse carrying excess memory T cells
    2009  [Not refereed][Not invited]
  • Hepatic IL-7 Regulates CD4+T Cell-mediated Autoimmune diseases.
    2009  [Not refereed][Not invited]
  • 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  2009/01  [Not refereed][Not invited]
     
    Infection with pathogens containing superantigens (Sags) can result in massive excessive CD4(+) T cell activation and death in such conditions as toxic shock, food poisoning and autoimmune diseases. We here showed how enhancement of IL-6 signaling suppresses Sag-mediated activated CD4(+) T cell death. Sag-induced CD4(+) T cell death increased in IL-6 knockout (KO) mice, whereas it decreased in mice characterized by enhanced IL-6-gp130-STAT3 signaling. The serum concentration of IFN-gamma was inversely correlated with the magnitude of IL-6 signaling, and IFN-gamma deficiency inhibited Sag-induced activated CD4(+) T cell death, suggesting that IL-6 suppresses CD4(+) T cell death via IFN-gamma expression. Interestingly, depletion of activated CD8(+) T cells inhibited Sag-mediated increases in IFN-gamma expression in IL-6 KO mice as well as the augmented CD4(+) T cell death. The results demonstrate that IL-6-gp130-STAT3 signaling in activated CD8(+) T cells contributes to Sag-induced CD4(+) T cell death via IFN-gamma expression, highlighting this signaling axis in CD8(+) T cells as a potential therapeutic target for Sag-related syndromes.
  • Liver as a regulator of T cells
    2009  [Not refereed][Not invited]
  • Zinc prevents Th17 cell-mediated autoimmune disease by directly inhibiting STAT3
    2009  [Not refereed][Not invited]
  • 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  [Not refereed][Not invited]
  • The recognition of specific antigens is not always required for the development of tissue-specific autoimmune diseases associated with MHC II.
    2009  [Not refereed][Not invited]
  • Foxp3+CD8+ T cells inhibit the development of F759 arthritis.
    2009  [Not refereed][Not invited]
  • 亜鉛シグナルの標的分子の探索と解析
    2009  [Not refereed][Not invited]
  • Zinc prevents Th17 cell-mediated autoimmune disease by directly inhibiting STAT3
    2009  [Not refereed][Not invited]
  • Foxp3+CD8+ T cells inhibit the development of F759 arthritis.
    2009  [Not refereed][Not invited]
  • Impaired STAT activations in an ENU mutant mouse carrying excess memory T cells
    2009  [Not refereed][Not invited]
  • 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  2009/01  [Not refereed][Not invited]
     
    Infection with pathogens containing superantigens (Sags) can result in massive excessive CD4(+) T cell activation and death in such conditions as toxic shock, food poisoning and autoimmune diseases. We here showed how enhancement of IL-6 signaling suppresses Sag-mediated activated CD4(+) T cell death. Sag-induced CD4(+) T cell death increased in IL-6 knockout (KO) mice, whereas it decreased in mice characterized by enhanced IL-6-gp130-STAT3 signaling. The serum concentration of IFN-gamma was inversely correlated with the magnitude of IL-6 signaling, and IFN-gamma deficiency inhibited Sag-induced activated CD4(+) T cell death, suggesting that IL-6 suppresses CD4(+) T cell death via IFN-gamma expression. Interestingly, depletion of activated CD8(+) T cells inhibited Sag-mediated increases in IFN-gamma expression in IL-6 KO mice as well as the augmented CD4(+) T cell death. The results demonstrate that IL-6-gp130-STAT3 signaling in activated CD8(+) T cells contributes to Sag-induced CD4(+) T cell death via IFN-gamma expression, highlighting this signaling axis in CD8(+) T cells as a potential therapeutic target for Sag-related syndromes.
  • Liver as a regulator of T cells
    2009  [Not refereed][Not invited]
  • IL-6アンプと炎症性疾患
    細胞工学  28(11):1107-1112, 2009-  2009  [Not refereed][Not invited]
  • 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  [Not refereed][Not invited]
  • Hepatic IL-7 Regulates CD4+T Cell-mediated Autoimmune diseases.
    2009  [Not refereed][Not invited]
  • Yoshinori Tanaka, Nobuyuki Tanaka, Yasushi Saeki, Keiji Tanaka, Masaaki Murakami, Toshio Hirano, Naoto Ishii, Kazuo Sugamura  MOLECULAR AND CELLULAR BIOLOGY  28-  (15)  4805  -4818  2008/08  [Not refereed][Not invited]
     
    Interieukin 6 (IL-6), a pleiotropic cytokine, functions in cells through its interaction with its receptor complex, which consists of two ligand-binding alpha subunits and two signal-transducing subunits known as gp130. There is a wealth of studies on signals mediated by gp130, but its downregulation is less well understood. Here we found that IL-6 stimulation induced lysosome-dependent degradation of gp130, which correlated with an increase in the K63-linked polyubiquitination of gp130. The stimulation-dependent ubiquitination of gp130 was mediated by c-Cb1, an E3 ligase, which was recruited to gp130 in a tyrosine-phosphorylated SHP2-dependent manner. We also found that IL-6 induced a rapid translocation of gp130 from the cell surface to endosomal compartments. Furthermore, the vesicular sorting molecule Hrs contributed to the lysosomal degradation of gp130 by directly recognizing its ubiquitinated form. Deficiency of either Hrs or c-Cbl suppressed gp130 degradation, which leads to a prolonged and amplified IL-6 signal. Thus, our present report provides the first evidence for involvement of a c-Cbl/SHP2 complex in ubiquitination and lysosomal degradation of gp130 upon IL-6 stimulation. The lysosomal degradation of gp130 is critical for cessation of IL-6-mediated signaling.
  • Yoshinori Tanaka, Nobuyuki Tanaka, Yasushi Saeki, Keiji Tanaka, Masaaki Murakami, Toshio Hirano, Naoto Ishii, Kazuo Sugamura  MOLECULAR AND CELLULAR BIOLOGY  28-  (15)  4805  -4818  2008/08  [Not refereed][Not invited]
     
    Interieukin 6 (IL-6), a pleiotropic cytokine, functions in cells through its interaction with its receptor complex, which consists of two ligand-binding alpha subunits and two signal-transducing subunits known as gp130. There is a wealth of studies on signals mediated by gp130, but its downregulation is less well understood. Here we found that IL-6 stimulation induced lysosome-dependent degradation of gp130, which correlated with an increase in the K63-linked polyubiquitination of gp130. The stimulation-dependent ubiquitination of gp130 was mediated by c-Cb1, an E3 ligase, which was recruited to gp130 in a tyrosine-phosphorylated SHP2-dependent manner. We also found that IL-6 induced a rapid translocation of gp130 from the cell surface to endosomal compartments. Furthermore, the vesicular sorting molecule Hrs contributed to the lysosomal degradation of gp130 by directly recognizing its ubiquitinated form. Deficiency of either Hrs or c-Cbl suppressed gp130 degradation, which leads to a prolonged and amplified IL-6 signal. Thus, our present report provides the first evidence for involvement of a c-Cbl/SHP2 complex in ubiquitination and lysosomal degradation of gp130 upon IL-6 stimulation. The lysosomal degradation of gp130 is critical for cessation of IL-6-mediated signaling.
  • Gui-Hua Jin, Toshio Hirano, Masaaki Murakami  INTERNATIONAL IMMUNOLOGY  20-  (6)  783  -789  2008/06  [Not refereed][Not invited]
     
    Combination treatment consisting of IL-2 together with anti-IL-2 mAbs results in markedly larger increases in the numbers of CD8(+) T cells, dendritic cells (DCs) and NK cells in vivo compared with the results observed with injections of IL-2 or the antibodies alone. We previously showed that this combination treatment overcomes the problems associated with the short half-life of IL-2 in vivo. Importantly, the combination treatment but not IL-2 or the anti-IL-2 mAbs alone protected the mice against tumor metastases in the lungs. Here we have investigated which cell types are responsible for this protective immunity against tumors. We analyzed tumor metastases in mice that were depleted of DCs, CD8(+) T cells or NK cells. DC-deficient, diphtheria toxin receptor-expressing mice injected with diphtheria toxin as well as B cell- and T cell-deficient RAG-2-knockout mice were protected against tumors after they were administered the combination treatment. On the other hand, mice that were depleted of NK cells using anti-asialo-GM1 antibodies did not exhibit the anti-tumor activity after treatment with IL-2 combined with anti-IL-2 mAbs. Thus, these data demonstrate that NK cells, but not DCs, or CD8(+) T cells mediate the anti-tumor effect induced by this combination treatment. Therefore, combining neutralizing anti-IL-2 mAbs with IL-2 may be clinically useful to effectively enhance IL-2-mediated NK cell activities.
  • Gui-Hua Jin, Toshio Hirano, Masaaki Murakami  INTERNATIONAL IMMUNOLOGY  20-  (6)  783  -789  2008/06  [Not refereed][Not invited]
     
    Combination treatment consisting of IL-2 together with anti-IL-2 mAbs results in markedly larger increases in the numbers of CD8(+) T cells, dendritic cells (DCs) and NK cells in vivo compared with the results observed with injections of IL-2 or the antibodies alone. We previously showed that this combination treatment overcomes the problems associated with the short half-life of IL-2 in vivo. Importantly, the combination treatment but not IL-2 or the anti-IL-2 mAbs alone protected the mice against tumor metastases in the lungs. Here we have investigated which cell types are responsible for this protective immunity against tumors. We analyzed tumor metastases in mice that were depleted of DCs, CD8(+) T cells or NK cells. DC-deficient, diphtheria toxin receptor-expressing mice injected with diphtheria toxin as well as B cell- and T cell-deficient RAG-2-knockout mice were protected against tumors after they were administered the combination treatment. On the other hand, mice that were depleted of NK cells using anti-asialo-GM1 antibodies did not exhibit the anti-tumor activity after treatment with IL-2 combined with anti-IL-2 mAbs. Thus, these data demonstrate that NK cells, but not DCs, or CD8(+) T cells mediate the anti-tumor effect induced by this combination treatment. Therefore, combining neutralizing anti-IL-2 mAbs with IL-2 may be clinically useful to effectively enhance IL-2-mediated NK cell activities.
  • Toshio Hirano, Masaaki Murakami, Toshiyuki Fukada, Keigo Nishida, Satoru Yamasaki, Tomoyuki Suzuki  ADVANCES IN IMMUNOLOGY, VOL 97  97-  149  -176  2008  [Not refereed][Not invited]
     
    Zinc (Zn) is an essential nutrient required for cell growth, differentiation, and survival, and its deficiency causes growth retardation, immunodeficiency, and other health problems. Therefore, Zn homeostasis must be tightly controlled in individual cells. Zn is known to be important in the immune system, although its precise roles and mechanisms have not yet been resolved. Zn has been suggested to act as a kind of neurotransmitter. In addition, Zn has been shown to bind and affect the activity of several signaling molecules, such as protein tyrosine phosphatases (PTPs). However, it has not been known whether Zn itself might act as an intracellular signaling molecule, that is, a molecule whose intracellular status is altered in response to an extracellular stimulus, and that is capable of transducing the extracellular stimulus into an intracellular signaling event. Here we propose that Zn acts as a signaling molecule and that there are at least two kinds of Zn signaling: "late Zn signaling," which is dependent on a change in the expression profile of Zn transporters, and "early Zn signaling," which involves a "Zn wave" and is directly induced by an extracellular stimulus. We also review recent progress in uncovering the roles of Zn in the immune system.
  • Dysregulation of an IL-17-Triggered Positive Feedback Loop of IL-6 Signaling in an Autoimmune Arthritis.
    Immunity  29: 628-636-  2008  [Not refereed][Not invited]
  • Toshio Hirano, Masaaki Murakami, Toshiyuki Fukada, Keigo Nishida, Satoru Yamasaki, Tomoyuki Suzuki  ADVANCES IN IMMUNOLOGY, VOL 97  97-  149  -176  2008  [Not refereed][Not invited]
     
    Zinc (Zn) is an essential nutrient required for cell growth, differentiation, and survival, and its deficiency causes growth retardation, immunodeficiency, and other health problems. Therefore, Zn homeostasis must be tightly controlled in individual cells. Zn is known to be important in the immune system, although its precise roles and mechanisms have not yet been resolved. Zn has been suggested to act as a kind of neurotransmitter. In addition, Zn has been shown to bind and affect the activity of several signaling molecules, such as protein tyrosine phosphatases (PTPs). However, it has not been known whether Zn itself might act as an intracellular signaling molecule, that is, a molecule whose intracellular status is altered in response to an extracellular stimulus, and that is capable of transducing the extracellular stimulus into an intracellular signaling event. Here we propose that Zn acts as a signaling molecule and that there are at least two kinds of Zn signaling: "late Zn signaling," which is dependent on a change in the expression profile of Zn transporters, and "early Zn signaling," which involves a "Zn wave" and is directly induced by an extracellular stimulus. We also review recent progress in uncovering the roles of Zn in the immune system.
  • Cancer Science  99:1515-22-  2008  [Not refereed][Not invited]
  • Cancer Science  99:1515-22-  2008  [Not refereed][Not invited]
  • Dysregulation of an IL-17-Triggered Positive Feedback Loop of IL-6 Signaling in an Autoimmune Arthritis.
    Immunity  29: 628-636-  2008  [Not refereed][Not invited]
  • 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  2007/06  [Not refereed][Not invited]
     
    IL-17-producing T-h (T(h)17) comprise a distinct lineage of pro-inflammatory T-h that are major contributors to autoimmune diseases. Treatment with IL-6 and transforming growth factor beta (TGF beta) induces naive CD4(+) T cells to generate Th17, which also requires expression of the IL-6/TGF[3 target ROR gamma t. We reported that IL-6 transduces two signaling pathways via tyrosine redidues of the signal transducer gp130: one depends on signal transducers and activators of transcription (STAT)-3 activation and the other on Src homology region 2 domain-containing phosphatase 2 (SHP2)/Grb2 associated binder (Gab)/mitogen-activated protein kinase (MAPK) activation. Here, we showed that CD4+ T cells carrying a mutant gp130 that transduces the SHP2/Gab/MAPK pathway but not the STAT3-mediated one failed to develop into Th17, while CD4+ T cells whose mutant gp130 transduces the STAT3 signal only generated Th17, indicating that IL-6 acts directly on T cells through the tyrosine residues of gp130 required for STAT3 activation to promote the development of Th17. Moreover, we found that gp130-STAT3 pathway is essential for Th17 development and for the expression of ROR gamma t by using T cells specifically lacking gp130 and STAT3. Noteworthy is that the regulatory T cell (Treg) percentages and numbers were comparable between all mutant mice we tested in vivo, although we showed that IL-6-gp130-STAT3 pathway suppressed Treg development in vitro. Thus, we conclude that IL-6 acts directly to promote the development of Th17 by activating the T cell gp130-STAT3 pathway but has a minimum effect on Treg development at least in the steady state in vivo. Therefore, blockade of IL-6-gp130-STAT3 pathway in CD4+ T cells could be a good target for controlling unwanted T(h)17-mediated immune responses including autoimmune diseases.
  • 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  2007/06  [Not refereed][Not invited]
     
    IL-17-producing T-h (T(h)17) comprise a distinct lineage of pro-inflammatory T-h that are major contributors to autoimmune diseases. Treatment with IL-6 and transforming growth factor beta (TGF beta) induces naive CD4(+) T cells to generate Th17, which also requires expression of the IL-6/TGF[3 target ROR gamma t. We reported that IL-6 transduces two signaling pathways via tyrosine redidues of the signal transducer gp130: one depends on signal transducers and activators of transcription (STAT)-3 activation and the other on Src homology region 2 domain-containing phosphatase 2 (SHP2)/Grb2 associated binder (Gab)/mitogen-activated protein kinase (MAPK) activation. Here, we showed that CD4+ T cells carrying a mutant gp130 that transduces the SHP2/Gab/MAPK pathway but not the STAT3-mediated one failed to develop into Th17, while CD4+ T cells whose mutant gp130 transduces the STAT3 signal only generated Th17, indicating that IL-6 acts directly on T cells through the tyrosine residues of gp130 required for STAT3 activation to promote the development of Th17. Moreover, we found that gp130-STAT3 pathway is essential for Th17 development and for the expression of ROR gamma t by using T cells specifically lacking gp130 and STAT3. Noteworthy is that the regulatory T cell (Treg) percentages and numbers were comparable between all mutant mice we tested in vivo, although we showed that IL-6-gp130-STAT3 pathway suppressed Treg development in vitro. Thus, we conclude that IL-6 acts directly to promote the development of Th17 by activating the T cell gp130-STAT3 pathway but has a minimum effect on Treg development at least in the steady state in vivo. Therefore, blockade of IL-6-gp130-STAT3 pathway in CD4+ T cells could be a good target for controlling unwanted T(h)17-mediated immune responses including autoimmune diseases.
  • 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  [Not refereed][Not invited]
  • Guihua Jin, Masaaki Murakami, and Toshio Hirano
    2007  [Not refereed][Not invited]
  • IL-6 inhibits PLCg activation in TCR-mediated signaling
    2007  [Not refereed][Not invited]
  • Guihua Jin, Masaaki Murakami, and Toshio Hirano
    2007  [Not refereed][Not invited]
  • 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  [Not refereed][Not invited]
  • Antigen independent induction of a CD4+ T cell-dependent arthritis.
    2007  [Not refereed][Not invited]
  • IL-6 inhibits PLCg activation in TCR-mediated signaling
    2007  [Not refereed][Not invited]
  • Antigen independent induction of a CD4+ T cell-dependent arthritis.
    2007  [Not refereed][Not invited]
  • Liver acute-phase reactions convert innate immune signaling into adaptive immune responses
    2007  [Not refereed][Not invited]
  • Liver acute-phase reactions convert innate immune signaling into adaptive immune responses
    2007  [Not refereed][Not invited]
  • 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  2006/09  [Not refereed][Not invited]
     
    Zinc is a trace element that is essential for the function of many enzymes and transcription factors. Zinc deficiency results in defects in innate and acquired immune responses. However, little is known about the mechanism(s) by which zinc affects immune cell function. Here we show that stimulation with the Toll-like receptor 4 agonist lipopolysaccharide (LPS) altered the expression of zinc transporters in dendritic cells and thereby decreased intracellular free zinc. A zinc chelator mimicked the effects of LPS, whereas zinc supplementation or overexpression of the gene encoding Zip6, a zinc transporter whose expression was reduced by LPS, inhibited LPS-induced upregulation of major histocompatibility complex class II and costimulatory molecules. These results establish a link between Toll-like receptor signaling and zinc homeostasis.
  • 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  2006/09  [Not refereed][Not invited]
     
    Zinc is a trace element that is essential for the function of many enzymes and transcription factors. Zinc deficiency results in defects in innate and acquired immune responses. However, little is known about the mechanism(s) by which zinc affects immune cell function. Here we show that stimulation with the Toll-like receptor 4 agonist lipopolysaccharide (LPS) altered the expression of zinc transporters in dendritic cells and thereby decreased intracellular free zinc. A zinc chelator mimicked the effects of LPS, whereas zinc supplementation or overexpression of the gene encoding Zip6, a zinc transporter whose expression was reduced by LPS, inhibited LPS-induced upregulation of major histocompatibility complex class II and costimulatory molecules. These results establish a link between Toll-like receptor signaling and zinc homeostasis.
  • 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  2006/09  [Not refereed][Not invited]
     
    CD1d-restricted NKT cells are activated by TCR-mediated stimulation via CD1d plus lipid antigens such as alpha-galactosylceramide (alpha-GaICer). These cells suppressed autoimmunity and graft rejection, but sometimes enhanced resistance to infection and tumor immunity. This double-action phenomenon of NKT cells is partly explained by cytokines produced by NKT cells. Therefore, roles of cytokines from activated NKT cells have been extensively examined; however, their roles on T cell homeostatic proliferation in lymphopenic condition have not been investigated. Here, we showed that alpha-GaICer enhanced homeostatic proliferation of CD8(+) but not CD4(+) T cells and this effect of alpha-GaICer was required for NKT cells. IL-4 was essential and sufficient for this NKT cell action on CD8(+) T cell homeostatic proliferation. Importantly, the expression of IL-4R alpha and STAT6 in CD8(+) T cells was essential for the NKT activity, indicating a direct action of IL-4 on CD8(+) T cells. Consistent with this, the level of IL-4R alpha expression on memory phenotype CD8(+) T cells was higher than that on naive phenotype one and CD4(+) T cells. Thus, these results showed the 'involvement' of IL-4 that is produced from activated NKT cells for CD8(+) T cell homeostatic proliferation in vivo.
  • 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  2006/09  [Not refereed][Not invited]
     
    CD1d-restricted NKT cells are activated by TCR-mediated stimulation via CD1d plus lipid antigens such as alpha-galactosylceramide (alpha-GaICer). These cells suppressed autoimmunity and graft rejection, but sometimes enhanced resistance to infection and tumor immunity. This double-action phenomenon of NKT cells is partly explained by cytokines produced by NKT cells. Therefore, roles of cytokines from activated NKT cells have been extensively examined; however, their roles on T cell homeostatic proliferation in lymphopenic condition have not been investigated. Here, we showed that alpha-GaICer enhanced homeostatic proliferation of CD8(+) but not CD4(+) T cells and this effect of alpha-GaICer was required for NKT cells. IL-4 was essential and sufficient for this NKT cell action on CD8(+) T cell homeostatic proliferation. Importantly, the expression of IL-4R alpha and STAT6 in CD8(+) T cells was essential for the NKT activity, indicating a direct action of IL-4 on CD8(+) T cells. Consistent with this, the level of IL-4R alpha expression on memory phenotype CD8(+) T cells was higher than that on naive phenotype one and CD4(+) T cells. Thus, these results showed the 'involvement' of IL-4 that is produced from activated NKT cells for CD8(+) T cell homeostatic proliferation in vivo.
  • 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  2006/07  [Not refereed][Not invited]
     
    IL-2 is a potent immunostimulant and has been tested for clinical use, including in immunotherapy for cancers and HIV infection. Here we show that a widely used neutralizing anti-murine IL-2 mAb (S4B6) exhibits unexpected activities that enhance the treatment effects of IL-2 in vivo. Coinjection of the anti-IL-2 mAb with a plasmid carrying murine IL-2 eDNA significantly increased the serum IL-2 levels and induced a substantial increase in the division of CD8(+) T and NK1.1(high) cells in vivo. Injection of the mAb premixed with recombinant murine IL-2 showed the same enhanced effect. A 5-day treatment with the anti-IL-2 mAb alone gradually increased the CD44(high)CD8(+) population, and the increased population was maintained for > 300 days, suggesting that the mAb can gradually maintain and potentially enhance the bioactivity of endogenous IL-2 for extended periods. Furthermore, combined treatment with the anti-IL-2 mAb plus the IL-2 plasmid markedly enhanced Ag-specific CTL activity in vivo and partially protected mice from tumor metastasis to the lungs, compared with the anti-IL-2 mAb or IL-2 plasmid alone. These results demonstrated IL-2-enhancing effects of the anti-IL-2 mAb in vivo and suggest that combining a neutralizing anti-IL-2 Ab with IL-2 gene delivery might be used effectively to enhance IL-2 functions in clinical applications.
  • 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  2006/07  [Not refereed][Not invited]
     
    IL-2 is a potent immunostimulant and has been tested for clinical use, including in immunotherapy for cancers and HIV infection. Here we show that a widely used neutralizing anti-murine IL-2 mAb (S4B6) exhibits unexpected activities that enhance the treatment effects of IL-2 in vivo. Coinjection of the anti-IL-2 mAb with a plasmid carrying murine IL-2 eDNA significantly increased the serum IL-2 levels and induced a substantial increase in the division of CD8(+) T and NK1.1(high) cells in vivo. Injection of the mAb premixed with recombinant murine IL-2 showed the same enhanced effect. A 5-day treatment with the anti-IL-2 mAb alone gradually increased the CD44(high)CD8(+) population, and the increased population was maintained for > 300 days, suggesting that the mAb can gradually maintain and potentially enhance the bioactivity of endogenous IL-2 for extended periods. Furthermore, combined treatment with the anti-IL-2 mAb plus the IL-2 plasmid markedly enhanced Ag-specific CTL activity in vivo and partially protected mice from tumor metastasis to the lungs, compared with the anti-IL-2 mAb or IL-2 plasmid alone. These results demonstrated IL-2-enhancing effects of the anti-IL-2 mAb in vivo and suggest that combining a neutralizing anti-IL-2 Ab with IL-2 gene delivery might be used effectively to enhance IL-2 functions in clinical applications.
  • 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  2006/06  [Not refereed][Not invited]
     
    Mice homozygous for the F759 mutation in the gp130 interleukin ( IL)-6 receptor subunit have enhanced gp130-mediated signal transducer and activator of transcription ( STAT)3 activation and spontaneously developed a lymphocyte-mediated rheumatoid arthritis-like joint disease. Here, we show that the development of the disease is dependent on both major histocompatibility complex ( MHC)II-restricted CD4(+) T cells and IL-6 family cytokines. In spite of the necessity for CD4(+) T cells, the gp130 mutation was only required in nonhemtopoietic cells for the disease. The gp130 mutation resulted in enhanced production of IL-7. Conditional knockout of STAT3 in nonlymphoid cells showed that the enhancement of IL-7 production was dependent on STAT3 activation by IL-6 family cytokines. Homeostatic proliferation of CD4(+) T cells was enhanced in gp130 mutant mice and acceleration of homeostatic proliferation enhanced the disease, whereas the inhibition of homeostatic proliferation suppressed the disease. Anti-IL-7 antibody treatment inhibited not only the enhanced homeostatic proliferation, but also the disease in gp130 mutant mice. Thus, our results show that autoimmune disease in gp130 mutant mice is caused by increased homeostatic proliferation of CD4(+) T cells, which is due to elevated production of IL-7 by nonhematopoietic cells as a result of IL-6 family cytokine-gp130-STAT3 signaling.
  • 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  2006/06  [Not refereed][Not invited]
     
    Mice homozygous for the F759 mutation in the gp130 interleukin ( IL)-6 receptor subunit have enhanced gp130-mediated signal transducer and activator of transcription ( STAT)3 activation and spontaneously developed a lymphocyte-mediated rheumatoid arthritis-like joint disease. Here, we show that the development of the disease is dependent on both major histocompatibility complex ( MHC)II-restricted CD4(+) T cells and IL-6 family cytokines. In spite of the necessity for CD4(+) T cells, the gp130 mutation was only required in nonhemtopoietic cells for the disease. The gp130 mutation resulted in enhanced production of IL-7. Conditional knockout of STAT3 in nonlymphoid cells showed that the enhancement of IL-7 production was dependent on STAT3 activation by IL-6 family cytokines. Homeostatic proliferation of CD4(+) T cells was enhanced in gp130 mutant mice and acceleration of homeostatic proliferation enhanced the disease, whereas the inhibition of homeostatic proliferation suppressed the disease. Anti-IL-7 antibody treatment inhibited not only the enhanced homeostatic proliferation, but also the disease in gp130 mutant mice. Thus, our results show that autoimmune disease in gp130 mutant mice is caused by increased homeostatic proliferation of CD4(+) T cells, which is due to elevated production of IL-7 by nonhematopoietic cells as a result of IL-6 family cytokine-gp130-STAT3 signaling.
  • T Hirano, M Murakami  DEVELOPMENTAL CELL  10-  (5)  542  -544  2006/05  [Not refereed][Not invited]
     
    Signaling via suppressors of cytokine signaling (SOCS) is an important negative feedback system for cytokine-mediated signal transduction. Recently in Molecular Cell, Babon et al. (2006) described the tertiary structure of SOCS3 in complex with a phosphotyrosine-containing peptide from the IL-6 receptor sub-unit gp130, and they identified the specific amino acids that are critical for binding.
  • Dev. Cell  10:542-544-  2006  [Not refereed][Not invited]
  • H Kitamura, H Kamon, SI Sawa, SJ Park, N Katunuma, K Ishihara, M Murakami, T Hirano  IMMUNITY  23-  (5)  491  -502  2005/11  [Not refereed][Not invited]
     
    We found IL-6-STAT3 pathway suppresses MHC class II (MHCII) expression on dendritic cells (DCs) and attenuates T cell activation. Here, we showed that IL-6-STAT3 signaling reduced intracellular MHCII alpha beta dimmer, Ii, and H2-DM levels in DCs. IL-6-mediated STAT3 activation decreased cystatin C level, an endogenous inhibitor of cathepsins, and enhanced cathepsin activities. Importantly, cathepsin S inhibitors blocked reduction of MHCII alpha beta dimer, Ii, and H2-DM in the IL-6-treated DCs. Overexpression of cystatin C suppressed IL-6-STAT3-mediated increase of cathepsin S activity and reduction of MHCII alpha beta dimer, Ii, and H2-DM levels in DCs. Cathepsin S overexpression in DCs decreased intracellular MHCII alpha beta dimer, Ii, and H2-DM levels, LPS-mediated surface expression of MHCII and suppressed CD4(+) T cell activation. IL-6-gp130-STAT3 signaling in vivo decreased cystatin C expression and MHCII alpha beta dimer level in DCs. Thus, IL-6-STAT3-mediated increase of cathepsin S activity reduces the MHCII alpha beta dimer, Ii, and H2-DM levels in DCs, and suppresses CD4(+) T cell-mediated immune responses.
  • H Kitamura, H Kamon, SI Sawa, SJ Park, N Katunuma, K Ishihara, M Murakami, T Hirano  IMMUNITY  23-  (5)  491  -502  2005/11  [Not refereed][Not invited]
     
    We found IL-6-STAT3 pathway suppresses MHC class II (MHCII) expression on dendritic cells (DCs) and attenuates T cell activation. Here, we showed that IL-6-STAT3 signaling reduced intracellular MHCII alpha beta dimmer, Ii, and H2-DM levels in DCs. IL-6-mediated STAT3 activation decreased cystatin C level, an endogenous inhibitor of cathepsins, and enhanced cathepsin activities. Importantly, cathepsin S inhibitors blocked reduction of MHCII alpha beta dimer, Ii, and H2-DM in the IL-6-treated DCs. Overexpression of cystatin C suppressed IL-6-STAT3-mediated increase of cathepsin S activity and reduction of MHCII alpha beta dimer, Ii, and H2-DM levels in DCs. Cathepsin S overexpression in DCs decreased intracellular MHCII alpha beta dimer, Ii, and H2-DM levels, LPS-mediated surface expression of MHCII and suppressed CD4(+) T cell activation. IL-6-gp130-STAT3 signaling in vivo decreased cystatin C expression and MHCII alpha beta dimer level in DCs. Thus, IL-6-STAT3-mediated increase of cathepsin S activity reduces the MHCII alpha beta dimer, Ii, and H2-DM levels in DCs, and suppresses CD4(+) T cell-mediated immune responses.
  • H Kitamura, H Kamon, SI Sawa, SJ Park, N Katunuma, K Ishihara, M Murakami, T Hirano  IMMUNITY  23-  (5)  491  -502  2005/11  [Not refereed][Not invited]
     
    We found IL-6-STAT3 pathway suppresses MHC class II (MHCII) expression on dendritic cells (DCs) and attenuates T cell activation. Here, we showed that IL-6-STAT3 signaling reduced intracellular MHCII alpha beta dimmer, Ii, and H2-DM levels in DCs. IL-6-mediated STAT3 activation decreased cystatin C level, an endogenous inhibitor of cathepsins, and enhanced cathepsin activities. Importantly, cathepsin S inhibitors blocked reduction of MHCII alpha beta dimer, Ii, and H2-DM in the IL-6-treated DCs. Overexpression of cystatin C suppressed IL-6-STAT3-mediated increase of cathepsin S activity and reduction of MHCII alpha beta dimer, Ii, and H2-DM levels in DCs. Cathepsin S overexpression in DCs decreased intracellular MHCII alpha beta dimer, Ii, and H2-DM levels, LPS-mediated surface expression of MHCII and suppressed CD4(+) T cell activation. IL-6-gp130-STAT3 signaling in vivo decreased cystatin C expression and MHCII alpha beta dimer level in DCs. Thus, IL-6-STAT3-mediated increase of cathepsin S activity reduces the MHCII alpha beta dimer, Ii, and H2-DM levels in DCs, and suppresses CD4(+) T cell-mediated immune responses.
  • H Kitamura, H Kamon, SI Sawa, SJ Park, N Katunuma, K Ishihara, M Murakami, T Hirano  IMMUNITY  23-  (5)  491  -502  2005/11  [Not refereed][Not invited]
     
    We found IL-6-STAT3 pathway suppresses MHC class II (MHCII) expression on dendritic cells (DCs) and attenuates T cell activation. Here, we showed that IL-6-STAT3 signaling reduced intracellular MHCII alpha beta dimmer, Ii, and H2-DM levels in DCs. IL-6-mediated STAT3 activation decreased cystatin C level, an endogenous inhibitor of cathepsins, and enhanced cathepsin activities. Importantly, cathepsin S inhibitors blocked reduction of MHCII alpha beta dimer, Ii, and H2-DM in the IL-6-treated DCs. Overexpression of cystatin C suppressed IL-6-STAT3-mediated increase of cathepsin S activity and reduction of MHCII alpha beta dimer, Ii, and H2-DM levels in DCs. Cathepsin S overexpression in DCs decreased intracellular MHCII alpha beta dimer, Ii, and H2-DM levels, LPS-mediated surface expression of MHCII and suppressed CD4(+) T cell activation. IL-6-gp130-STAT3 signaling in vivo decreased cystatin C expression and MHCII alpha beta dimer level in DCs. Thus, IL-6-STAT3-mediated increase of cathepsin S activity reduces the MHCII alpha beta dimer, Ii, and H2-DM levels in DCs, and suppresses CD4(+) T cell-mediated immune responses.
  • 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  2004/11  [Not refereed][Not invited]
     
    The homeostasis of memory CD8(+) T cells is regulated by cytokines. IL-15 is shown to promote the proliferation of memory CD8(+) T cells, while IL-2 suppresses their division in vivo. This inhibitory effect of IL-2 appears to occur indirectly, through other cell populations including CD25(+)CD4(+) T cells; however, the details of this mechanism remain unclear. In this study, we show that 1) both Ag-experienced and memory phenotype CD8(+) T cells divided after the depletion of IL-2 in vivo; 2) this division occurred normally and CD44(high)IL-2/15Rbeta(high) CD8(+) T cells generated after IL-2 depletion in IL-15 knockout (KO) and in IL-7-depleted IL-15 KO mice; 3) surprisingly, the blockade of IL-2/15Rbeta signaling in IL-2-depleted IL-15 KO mice completely abolished the division of memory CD8(+) T cells, although the only cytokines known to act through IL-2/15Rbeta are IL-2 and IL-15; and 4) the expression of IL-2/15Rbeta molecules on memory CD8(+) T cells was required for their division induced by IL-2 depletion. These results demonstrate that the depletion of IL-2 in vivo induced memory CD8(+) T cell division by an IL-15-independent but by an IL-2/15Rbeta-dependent mechanism, suggesting the existence of a novel IL-2/15Rbeta-utilizing cytokine that acts directly on memory CD8(+) T cells to promote cell division.
  • T Mizutani, S Fukushi, M Murakami, T Hirano, M Saijo, Kurane, I, S Morikawa  FEBS LETTERS  577-  (1-2)  187  -192  2004/11  [Not refereed][Not invited]
     
    Severe acute respiratory syndrome (SARS) has become a global public health emergency. p38 mitogen-activated protein kinase (MAPK) and its downstream targets are activated in SARS coronavirus (SARS-CoV)-infected Vero E6 cells and activation of p38 MAPK enhances the cytopathic effects of SARS-CoV infection. In addition, weak activation of Akt cannot prevent SARS-CoV infection-induced apoptosis in Vero E6 cells. In the present study, we demonstrated that signal transducer and activator of transcription (STAT) 3, which is constitutively phosphorylated at tyrosine (Tyr)-705 and slightly phosphorylated at serine (Ser)-727 in Vero E6 cells, was dephosphorylated at Tyr-705 on SARS-CoV infection. In addition to phosphorylation of p38 MAPK in virus-infected cells, other MAPKs, i.e., extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK), were phosphorylated. Although inhibitors of ERK 1/2 and JNK (PD98059 and SP600125) bad no effect on phosphorylation status of STAT3, inhibitors of p38 MAPK (SB203580 and SB202190) partially inhibited dephosphorylation of STAT3 at Tyr-705. Tyr-705-phosphorylated STAT3 was localized mainly in the nucleus in mock infected cells, whereas STAT3 disappeared from the nucleus in virus-infected cells. As STAT3 acts as an activator of transcription in the nucleus, these results suggest that STAT3 lacks its activity on transcription in SARS-CoV-infected Vero E6 cells. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
  • T Mizutani, S Fukushi, M Murakami, T Hirano, M Saijo, Kurane, I, S Morikawa  FEBS LETTERS  577-  (1-2)  187  -192  2004/11  [Not refereed][Not invited]
     
    Severe acute respiratory syndrome (SARS) has become a global public health emergency. p38 mitogen-activated protein kinase (MAPK) and its downstream targets are activated in SARS coronavirus (SARS-CoV)-infected Vero E6 cells and activation of p38 MAPK enhances the cytopathic effects of SARS-CoV infection. In addition, weak activation of Akt cannot prevent SARS-CoV infection-induced apoptosis in Vero E6 cells. In the present study, we demonstrated that signal transducer and activator of transcription (STAT) 3, which is constitutively phosphorylated at tyrosine (Tyr)-705 and slightly phosphorylated at serine (Ser)-727 in Vero E6 cells, was dephosphorylated at Tyr-705 on SARS-CoV infection. In addition to phosphorylation of p38 MAPK in virus-infected cells, other MAPKs, i.e., extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK), were phosphorylated. Although inhibitors of ERK 1/2 and JNK (PD98059 and SP600125) bad no effect on phosphorylation status of STAT3, inhibitors of p38 MAPK (SB203580 and SB202190) partially inhibited dephosphorylation of STAT3 at Tyr-705. Tyr-705-phosphorylated STAT3 was localized mainly in the nucleus in mock infected cells, whereas STAT3 disappeared from the nucleus in virus-infected cells. As STAT3 acts as an activator of transcription in the nucleus, these results suggest that STAT3 lacks its activity on transcription in SARS-CoV-infected Vero E6 cells. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
  • 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  2004/11  [Not refereed][Not invited]
     
    The homeostasis of memory CD8(+) T cells is regulated by cytokines. IL-15 is shown to promote the proliferation of memory CD8(+) T cells, while IL-2 suppresses their division in vivo. This inhibitory effect of IL-2 appears to occur indirectly, through other cell populations including CD25(+)CD4(+) T cells; however, the details of this mechanism remain unclear. In this study, we show that 1) both Ag-experienced and memory phenotype CD8(+) T cells divided after the depletion of IL-2 in vivo; 2) this division occurred normally and CD44(high)IL-2/15Rbeta(high) CD8(+) T cells generated after IL-2 depletion in IL-15 knockout (KO) and in IL-7-depleted IL-15 KO mice; 3) surprisingly, the blockade of IL-2/15Rbeta signaling in IL-2-depleted IL-15 KO mice completely abolished the division of memory CD8(+) T cells, although the only cytokines known to act through IL-2/15Rbeta are IL-2 and IL-15; and 4) the expression of IL-2/15Rbeta molecules on memory CD8(+) T cells was required for their division induced by IL-2 depletion. These results demonstrate that the depletion of IL-2 in vivo induced memory CD8(+) T cell division by an IL-15-independent but by an IL-2/15Rbeta-dependent mechanism, suggesting the existence of a novel IL-2/15Rbeta-utilizing cytokine that acts directly on memory CD8(+) T cells to promote cell division.
  • 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  2004/09  [Not refereed][Not invited]
     
    Dendritic cells (DCs) orchestrate immune responses according to their state of maturation. In response to infection, DCs differentiate into mature cells that initiate immune responses, while in the absence of infection, most of them remain in an immature form that induces tolerance to self Ags. Understanding what controls these opposing effects is an important goal for vaccine development and prevention of unwanted immune responses. A crucial question is what cytokine(s) regulates DC maturation in the absence of infection. In this study, we show that IL-6 plays a major role in maintaining immature DCs. IL-6 knockout (KO) mice had increased numbers of mature DCs, indicating that IL-6 blocks DC maturation in vivo. We examined this effect further in knockin mice expressing mutant versions of the IL-6 signal transducer gp130, with defective signaling through either Src homology region 2 domain-containing phosphatase 2/Gab/MAPK (gp130 (F759/F759)) or STAT3 (gp130(FxxQ/FxxQ)), and combined gp130 and IL-6 defects (gp130(F759/F759)/IL-6 KO mice). Importantly, we found STAT3 activation by IL-6 was required for the suppression of LPS-induced DC maturation. In addition, STAT3 phosphorylation in DCs was regulated by IL-6 in vivo, and STAT3 was necessary for the IL-6 suppression of bone marrow-derived DC activation/maturation. DC-mediated T cell activation was enhanced in IL-6 KO mice and suppressed in gp130(F759/F759) mice. IL-6 is thus a potent regulator of DC differentiation in vivo, and IL-6-gp130-STAT3 signaling in DCs may represent a critical target for controlling T cell-mediated immune responses in vivo.
  • 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  2004/09  [Not refereed][Not invited]
     
    Dendritic cells (DCs) orchestrate immune responses according to their state of maturation. In response to infection, DCs differentiate into mature cells that initiate immune responses, while in the absence of infection, most of them remain in an immature form that induces tolerance to self Ags. Understanding what controls these opposing effects is an important goal for vaccine development and prevention of unwanted immune responses. A crucial question is what cytokine(s) regulates DC maturation in the absence of infection. In this study, we show that IL-6 plays a major role in maintaining immature DCs. IL-6 knockout (KO) mice had increased numbers of mature DCs, indicating that IL-6 blocks DC maturation in vivo. We examined this effect further in knockin mice expressing mutant versions of the IL-6 signal transducer gp130, with defective signaling through either Src homology region 2 domain-containing phosphatase 2/Gab/MAPK (gp130 (F759/F759)) or STAT3 (gp130(FxxQ/FxxQ)), and combined gp130 and IL-6 defects (gp130(F759/F759)/IL-6 KO mice). Importantly, we found STAT3 activation by IL-6 was required for the suppression of LPS-induced DC maturation. In addition, STAT3 phosphorylation in DCs was regulated by IL-6 in vivo, and STAT3 was necessary for the IL-6 suppression of bone marrow-derived DC activation/maturation. DC-mediated T cell activation was enhanced in IL-6 KO mice and suppressed in gp130(F759/F759) mice. IL-6 is thus a potent regulator of DC differentiation in vivo, and IL-6-gp130-STAT3 signaling in DCs may represent a critical target for controlling T cell-mediated immune responses in vivo.
  • Growth Factors.  22, 75-7.-  2004  [Not refereed][Not invited]
  • Growth Factors.  22, 75-7./,-  2004  [Not refereed][Not invited]
  • 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)  2001/03/10  [Not refereed][Not invited]
  • 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)  2000/03/10  [Not refereed][Not invited]
  • 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  2000/03  [Not refereed][Not invited]
     
    Background. CTLA4IgG that binds to B7 effectively inhibits the signaling of CD28/B7 pathway and induces antigen specific T-cell unresponsiveness in vitro and in vivo. We examined whether the development of obliterative bronchiolitis in a murine heterotopic airway transplantation model is T cell dependent and whether CTLA4IgG abrogates the development of obliterative bronchiolitis. Methods. Tracheae with main bronchi from C3H/He (H2(k)), BALB/C (H2(d)), or C57BL/6 (H2(b)) mice were transplanted heterotopic:ally into subcutaneous pockets on the backs of BALB/C or BALB/C nu/nu mice on day 0. Recipient mice were untreated or intraperitoneally treated with either CTLA4IgG or human IgG with different time and dose schedules. Results. The development of obliterative bronchiolitis, which leads to luminal obliteration by fibrous tissue in a murine heterotopic airway transplantation model, was T cell dependent and the development of obliterative bronchiolitis was significantly abrogated by the CTLA4IgG treatment. However, the normal ciliated columnar respiratory epithelial cells in allografts were lost and replaced by flattened attenuated epithelial cells even after the CTLA4IgG treatment. We further demonstrated that CTLA4IgG treatment did not result in the induction of donor-specific unresponsiveness. Conclusions. We demonstrated that the development of obliterative bronchiolitis in a murine heterotopic airway model involves both CD28/B7-dependent and -independent processes. The luminal obliteration by fibrous tissue is clearly CD28/B7 dependent and can be inhibited by CTLA4IgQ. The luminal obliteration of allografted trachea by fibrous tissues and the loss of ciliated columnar respiratory epithelial cells represent distinct disease processes.
  • 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  2000/03  [Not refereed][Not invited]
  • KU C C, MURAKAMI M, SAKAMOTO A, KAPPLER J, MARRACK P  Science  288-  (5466)  675  -678  2000  [Not refereed][Not invited]
  • 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  1999/09/01  [Not refereed][Not invited]
  • 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  1999/03/01  [Not refereed][Not invited]
  • 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)  1999/03/01  [Not refereed][Not invited]
  • 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-  1178  -1179  1999/02/01  [Not refereed][Not invited]
  • 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  1998/10  [Not refereed][Not invited]
  • 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  1998/08  [Not refereed][Not invited]
  • 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  1998/03  [Not refereed][Not invited]
  • 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  1998/03  [Not refereed][Not invited]
  • 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  1997/10  [Not refereed][Not invited]
  • 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  1997/10  [Not refereed][Not invited]
  • 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  1997/10  [Not refereed][Not invited]
  • Kaneda, R, Iwabuchi, K, Kasai, M, Murakami, M, Uede, T, Onoé, K  Cell. Immunol.  181-  (2)  163  -171  1997  [Not refereed][Not invited]
  • 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  1995/11  [Not refereed][Not invited]
     
    To examine the contribution of the angiotensin-converting enzyme (ACE) gene to hypertrophic cardiomyopathy (HCM), we determined the ACE insertion/deletion (I/D) polymorphism in 80 patients with HCM and 88 of their unaffected siblings and children. Patients were divided into familiar or solitary HCM (FHCM or SHCM) groups with or without affected family members. Genotypes were identified by the polymerase chain reaction (PCR) with oligonucleotide primers flanking the polymorphic region in intron 16 of the ACE gene to amplify template DNA prepared from peripheral leukocytes. D-allele frequencies were 0.38 in all subjects, 0.42 in patients with HCM, and 0.35 in relatives (p < 0.05). The probability ratios were 1.98, 1.46, and 2.97 in patients with HCM, FHCM, and SHCM, respectively. The D allele frequency was higher in SHCM than in FHCM (p < 0.05). The findings suggest that HCM, especially in solitary cases, is partially determined by genetic disposition. Findings imply that the ACE D allele is one of the genetic contributing factors associated with cardiac hypertrophy in HCM.

Educational Activities

Teaching Experience

  • 研究発表技法Ⅰ
    開講年度 : 2018
    課程区分 : 修士課程
    開講学部 : 医学院
  • Master's Thesis Research in Medical Sciences
    開講年度 : 2018
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : ゲートウェイ反射、炎症回路、免疫学、炎症学、神経免疫学、分子心理免疫学、自己免疫疾患、慢性炎症性疾患、サイトカイン、ヘルパーT細胞
  • 研究発表技法Ⅱ
    開講年度 : 2018
    課程区分 : 修士課程
    開講学部 : 医学院
  • Basic Principles of Medicine
    開講年度 : 2018
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : ゲートウェイ反射、炎症回路、免疫学、炎症学、神経免疫学、分子心理免疫学、自己免疫疾患、慢性炎症性疾患、サイトカイン、ヘルパーT細胞
  • 研究発表技法Ⅰ
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学研究科
  • Principles of Medicine
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : ゲートウェイ反射、炎症回路、免疫学、炎症学、神経免疫学、分子心理免疫学、自己免疫疾患、慢性炎症性疾患、サイトカイン、ヘルパーT細胞
  • 研究発表技法Ⅱ
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学研究科
  • Dissertation Research in Medical Sciences
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : ゲートウェイ反射、炎症回路、免疫学、炎症学、神経免疫学、分子心理免疫学、自己免疫疾患、慢性炎症性疾患、サイトカイン、ヘルパーT細胞
  • 基盤医学研究Ⅱ
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学研究科
  • 基盤医学研究Ⅰ
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学研究科
  • 医学総論
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学研究科
  • 研究発表技法Ⅰ
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学院
  • 研究発表技法Ⅱ
    開講年度 : 2018
    課程区分 : 博士後期課程
    開講学部 : 医学院

Campus Position History

  • 2016年4月1日 
    2018年3月31日 
    遺伝子病制御研究所長
  • 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 
    遺伝子病制御研究所長
  • 2018年4月1日 
    2020年3月31日 
    教育研究評議会評議員

Position History

  • 2016年4月1日 
    2018年3月31日 
    遺伝子病制御研究所長
  • 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 
    遺伝子病制御研究所長
  • 2018年4月1日 
    2020年3月31日 
    教育研究評議会評議員


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