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Takaoka Akinori

Institute for Genetic Medicine　Molecular PathogenesisProfessor

Researcher basic information

■ Degree
  • 博士（医学）, 札幌医科大学
■ URL
researchmap URLホームページURL■ Various IDs
J-Global ID■ Research Keywords and Fields
Research Field
  • Life Science, Immunology
  • Life Science, Medical biochemistry
■ Educational Organization

Career

■ Career
Career
  • Oct. 2017 - Present
    Hokkaido University, Institute for Genetic Medicine, 動物施設長
  • May 2007 - Present
    Hokkaido University, Institute for Genetic Medicine
  • Apr. 2012 - Mar. 2016
    Hokkaido University, Institute for Genetic Medicine
  • Jul. 2009 - Mar. 2012
    Hokkaido University, Institute for Genetic Medicine
  • 2002 - 2007
    東京大学医学部免疫学講座 講師
  • 2002 - 2007
    Lecturer
  • 2007
    - Professor
  • 2000 - 2002
    東京大学医学部免疫学講座 助手
  • 2000 - 2002
    Research Associate
  • 1997 - 2000
    東京大学医学部免疫学講座 日本学術振興会研究員（リサーチ・アソシエイト）
  • 1997 - 2000
    Research associate of the Japan Society for the Promotion of Science
  • 1996 - 1997
    東京大学医学部免疫学講座 研究員
  • 1996 - 1997
    Researcher
Educational Background
  • 1996, Sapporo Medical University, Graduate School of Medicine, 内科学, Japan
  • 1996, Sapporo Medical University, Graduate School, Division of Medicine
  • 1992, Sapporo Medical University, School of Medicine, Japan
  • 1992, Sapporo Medical University, Faculty of Medicine
Committee Memberships
  • Apr. 2014 - Present
    日本がん免疫学会, 理事, Society
  • Jan. 2014 - Present
    日本癌学会, 評議員, Society
  • Jun. 2013 - Present
    秋山記念生命科学振興財団, 評議員, Society
  • Apr. 2013 - Mar. 2015
    北海道医学会, 評議員, Society
  • 2007
    日本免疫学会, 評議員, Society
Position History
  • 遺伝子病制御研究所長, 2014年4月1日 - 2016年3月31日
  • 遺伝子病制御研究所附属動物実験施設長, 2017年11月1日 - 2018年3月31日
  • 遺伝子病制御研究所附属動物実験施設長, 2018年4月1日 - 2020年3月31日
  • 遺伝子病制御研究所附属動物実験施設長, 2020年4月1日 - 2022年3月31日
  • 教育研究評議会評議員, 2014年4月1日 - 2016年3月31日

Research activity information

■ Awards
  • Mar. 2015, 北海道大学 研究総長賞（優秀賞）
    髙岡 晃教
  • Mar. 2014, 北海道大学, 教育総長賞
    髙岡 晃教
  • Mar. 2013, 北海道大学 研究総長賞
    髙岡 晃教
  • 2011, 医学研究奨励賞 (日本医師会:日本)
    髙岡 晃教
  • 2005, 三菱化学奨励賞 (分子生物学会:日本)
    Japan
  • 2003, Milstein Young Investigator Award (インターフェロン・サイトカイン学会:オーストラリア）
  • 2003, 高松宮妃癌研究基金研究助成国際
    Japan
  • 2001, 奨励賞 (日本癌学会:日本)
    Japan
  • 2000, Young Investigator Award; 1st prize (国際サイトカイン学会:オランダ)
■ Papers
  • 17β-Estradiol (E2) Activates Matrix Mineralization through Genomic/Nongenomic Pathways in MC3T3-E1 Cells
    Hiraku Suzuki; Yuki Fujiwara; Winda Ariyani; Izuki Amano; Sumiyasu Ishii; Ayane Kate Ninomiya; Seiichi Sato; Akinori Takaoka; Noriyuki Koibuchi
    International Journal of Molecular Sciences, 26 Apr. 2024, [Peer-reviewed]
    Scientific journal
  • Augmented interferon regulatory factor 7 axis in whole tumor cell vaccines prevents tumor recurrence by inducing interferon gamma-secreting B cells
    Nabeel Kajihara; Yoshino Tanaka; Riko Takeuchi; Takuto Kobayashi; Masafumi Tanji; Tsukasa Ataka; Shiho Nakano; Taisho Yamada; Akinori Takaoka; Yoshinori Hasegawa; Ken-Ichiro Seino; Haruka Wada
    OncoImmunology, 12, 1, Informa UK Limited, 22 May 2023
    Scientific journal
  • Innate immune recognition against SARS-CoV-2
    Taisho Yamada; Akinori Takaoka
    Inflammation and Regeneration, 43, 1, Springer Science and Business Media LLC, 26 Jan. 2023
    Scientific journal, Abstract

    Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative virus of pandemic acute respiratory disease called coronavirus disease 2019 (COVID-19). Most of the infected individuals have asymptomatic or mild symptoms, but some patients show severe and critical systemic inflammation including tissue damage and multi-organ failures. Immune responses to the pathogen determine clinical course. In general, the activation of innate immune responses is mediated by host pattern-recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) as well as host damage-associated molecular patterns (DAMPs), which results in the activation of the downstream gene induction programs of types I and III interferons (IFNs) and proinflammatory cytokines for inducing antiviral activity. However, the excessive activation of these responses may lead to deleterious inflammation. Here, we review the recent advances in our understanding of innate immune responses to SARS-CoV-2 infection, particularly in terms of innate recognition and the subsequent inflammation underlying COVID-19 immunopathology.
  • Essential role of Rnd1 in innate immunity during viral and bacterial infections.
    Akhilesh Kumar; Shalabh Mishra; Ashish Kumar; Ashwin Ashok Raut; Seiichi Sato; Akinori Takaoka; Himanshu Kumar
    Cell death & disease, 13, 6, 520, 520, 02 Jun. 2022, [International Magazine]
    English, Scientific journal, Intracellular and cell surface pattern-recognition receptors (PRRs) are an essential part of innate immune recognition and host defense. Here, we have compared the innate immune responses between humans and bats to identify a novel membrane-associated protein, Rnd1, which defends against viral and bacterial infection in an interferon-independent manner. Rnd1 belongs to the Rho GTPase family, but unlike other small GTPase members, it is constitutively active. We show that Rnd1 is induced by pro-inflammatory cytokines during viral and bacterial infections and provides protection against these pathogens through two distinct mechanisms. Rnd1 counteracts intracellular calcium fluctuations by inhibiting RhoA activation, thereby inhibiting virus internalisation. On the other hand, Rnd1 also facilitates pro-inflammatory cytokines IL-6 and TNF-α through Plxnb1, which are highly effective against intracellular bacterial infections. These data provide a novel Rnd1-mediated innate defense against viral and bacterial infections.
  • Mindfulness intervention improves cognitive function in older adults by enhancing the level of miRNA-29c in neuron-derived extracellular vesicles
    Shin Hashizume; Masako Nakano; Kenta Kubota; Seiichi Sato; Nobuaki Himuro; Eiji Kobayashi; Akinori Takaoka; Mineko Fujimiya
    Scientific Reports, 11, 1, 21848, 21848, Springer Science and Business Media LLC, Dec. 2021, [Peer-reviewed], [International Magazine]
    English, Scientific journal, AbstractAlthough mindfulness-based stress reduction (MBSR) improves cognitive function, the mechanism is not clear. In this study, people aged 65 years and older were recruited from elderly communities in Chitose City, Japan, and assigned to a non-MBSR group or a MBSR group. Before and after the intervention, the Japanese version of the Montreal Cognitive Assessment (MoCA-J) was administered, and blood samples were collected. Then, neuron-derived extracellular vesicles (NDEVs) were isolated from blood samples, and microRNAs, as well as the target mRNAs, were evaluated in NDEVs. A linear mixed model analysis showed significant effects of the MBSR x time interaction on the MoCA-J scores, the expression of miRNA(miR)-29c, DNA methyltransferase 3 alpha (DNMT3A), and DNMT3B in NDEVs. These results indicate that MBSR can improve cognitive function by increasing the expression of miR-29c and decreasing the expression of DNMT3A, as well as DNMT3B, in neurons. It was also found that intracerebroventricular injection of miR-29c mimic into 5xFAD mice prevented cognitive decline, as well as neuronal loss in the subiculum area, by down-regulating Dnmt3a  and Dnmt3b  in the hippocampus. The present study suggests that MBSR can prevent neuronal loss and cognitive impairment by increasing the neuronal expression of miR-29c.
  • Dual Effect of Organogermanium Compound THGP on RIG-I-Mediated Viral Sensing and Viral Replication during Influenza a Virus Infection
    Sunanda Baidya; Yoko Nishimoto; Seiichi Sato; Yasuhiro Shimada; Nozomi Sakurai; Hirotaka Nonaka; Koki Noguchi; Mizuki Kido; Satoshi Tadano; Kozo Ishikawa; Kai Li; Aoi Okubo; Taisho Yamada; Yasuko Orba; Michihito Sasaki; Hirofumi Sawa; Hiroko Miyamoto; Ayato Takada; Takashi Nakamura; Akinori Takaoka
    Viruses, 13, 9, 1674, 1674, MDPI AG, 24 Aug. 2021
    Scientific journal, The interaction of viral nucleic acid with protein factors is a crucial process for initiating viral polymerase-mediated viral genome replication while activating pattern recognition receptor (PRR)-mediated innate immune responses. It has previously been reported that a hydrolysate of Ge-132, 3-(trihydroxygermyl) propanoic acid (THGP), shows a modulatory effect on microbial infections, inflammation, and immune responses. However, the detailed mechanism by which THGP can modify these processes during viral infections remained unknown. Here, we show that THGP can specifically downregulate type I interferon (IFN) production in response to stimulation with a cytosolic RNA sensor RIG-I ligand 5′-triphosphate RNA (3pRNA) but not double-stranded RNA, DNA, or lipopolysaccharide. Consistently, treatment with THGP resulted in the dose-dependent suppression of type I IFN induction upon infections with influenza virus (IAV) and vesicular stomatitis virus, which are known to be mainly sensed by RIG-I. Mechanistically, THGP directly binds to the 5′-triphosphate moiety of viral RNA and competes with RIG-I-mediated recognition. Furthermore, we found that THGP can directly counteract the replication of IAV but not EMCV (encephalitismyocarditis virus), by inhibiting the interaction of viral polymerase with RNA genome. Finally, IAV RNA levels were significantly reduced in the lung tissues of THGP-treated mice when compared with untreated mice. These results suggest a possible therapeutic implication of THGP and show direct antiviral action, together with the suppressive activity of innate inflammation.
  • RIG-I triggers a signaling-abortive anti-SARS-CoV-2 defense in human lung cells
    Taisho Yamada; Seiichi Sato; Yuki Sotoyama; Yasuko Orba; Hirofumi Sawa; Hajime Yamauchi; Michihito Sasaki; Akinori Takaoka
    Nature Immunology, 22, 7, 820, 828, Springer Science and Business Media LLC, Jul. 2021
    Scientific journal
  • Immunological modulators
    Akinori Takaoka; Seiichi Sato; Taisho Yamada
    Handbook of Hormones, 435, 435, Elsevier, 2021
    In book
  • Interleukins
    Seiichi Sato; Akinori Takaoka
    Handbook of Hormones, 437, 439, Elsevier, 2021
    In book
  • Regulation of an adaptor protein STING by Hsp90β to enhance innate immune responses against microbial infections.
    Seiichi Sato; Kai Li; Nozomi Sakurai; Mei Hashizume; Sunanda Baidya; Hirotaka Nonaka; Koki Noguchi; Kozo Ishikawa; Chikashi Obuse; Akinori Takaoka
    Cellular immunology, 356, 104188, 104188, 28 Jul. 2020, [Peer-reviewed], [International Magazine]
    English, Scientific journal, Stimulator of interferon genes (STING) plays important roles in the DNA-mediated innate immune responses. However, the regulatory mechanism of STING in terms of stabilization is not fully understood. Here, we identified the chaperone protein Hsp90s as novel STING interacting proteins. Treatment with an Hsp90 inhibitor 17-AAG and knockdown of Hsp90β but not Hsp90α reduced STING at protein level, resulted in the suppression of IFN induction in response to stimulation with cGAMP, and infections with HSV-1 and Listeria monocytogenes. Collectively, our results suggest that the control of STING protein by Hsp90β is a critical biological process in the DNA sensing pathways.
  • Immunosenescence: The forefront of infection and trophic control
    Mitsuo Maruyama; Akihiko Sakamoto; Yuji Morita; Akinori Takaoka
    Yakugaku Zasshi, 140, 3, 391, 393, Pharmaceutical Society of Japan, 01 Mar. 2020
    Japanese, International conference proceedings
  • Disinfectant potential in inactivation of epidemic keratoconjunctivitis-related adenoviruses by potassium peroxymonosulfate.
    Mei Hashizume; Koki Aoki; Shigeaki Ohno; Nobuyoshi Kitaichi; Nobuyo Yawata; Gabriel Gonzalez; Hirotaka Nonaka; Seiichi Sato; Akinori Takaoka
    European journal of ophthalmology, 31, 2, 1120672119891408, 1120672119891408, 09 Dec. 2019, [Peer-reviewed], [International Magazine]
    English, Scientific journal, PURPOSE: The aim of this study was to test the antiviral effectivity of potassium peroxymonosulfate (RUBYSTA®, KYORIN) against five epidemic keratoconjunctivitis-related types of Human adenovirus D in vitro. METHODS: Five types of Human adenovirus D (8, 37, 53, 54 and 56) were incubated with 1% potassium peroxymonosulfate, 0.1% sodium hypochlorite (NaClO) or alcohol-based disinfectant for 30 s or 1 min. These solutions were subjected to measurements of viral titres by infection assays in A549 cells. At day 6 post-infection, both, supernatants and cells, were collected and the viral genome was assessed by real-time polymerase chain reaction analysis. RESULTS: Treatments with 1% potassium peroxymonosulfate led to significant reduction in all tested Human adenovirus D types comparable to disinfecting effects by 0.1% NaClO. Overall, potassium peroxymonosulfate demonstrated sufficient inactivation of the major epidemic keratoconjunctivitis-causing Human adenovirus D to be considered for disinfection and prevention purposes in ophthalmological clinics and hospitals. CONCLUSION: This study demonstrated that potassium peroxymonosulfate is a promising disinfectant for the prevention of epidemic keratoconjunctivitis nosocomial infections in ophthalmological clinics.
  • BinCARD2 as a positive regulator of interferon response in innate immunity.
    Suzuki H; Kameyama T; Takaoka A
    Biochem Biophys Res Commun, 511, 2, 287, 293, Apr. 2019
  • Regulation of signaling mediated by nucleic acid sensors for innate interferon-mediated responses during viral infection.
    Takaoka A; Yamada T
    Int Immunol, 15, dxz034, Apr. 2019
  • The antiviral effects of human microRNA miR-302c-3p against hepatitis B virus infection.
    Hamada-Tsutsumi S; Naito Y; Sato S; Takaoka A; Kawashima K; Isogawa M; Ochiya T; Tanaka Y
    Aliment Pharmacol Ther, 49, 8, 1060, 1070, Apr. 2019, [International Magazine]
    English, Scientific journal, BACKGROUND: Conventional treatments of chronic hepatitis B virus (HBV) infection rarely achieve a decline of serum hepatitis B surface antigen (HBsAg) levels and eradication of the virus. AIM: To elucidate the antiviral mechanisms of a human microRNA, miR-302c-3p, against HBV replication. METHODS: The antiviral effect of miR-302c-3p was evaluated in vitro and in vivo by transfecting the miR-302c-3p mimic into HBV-infected HepG2-hNTCP-C4 cells and HBV transgenic mice respectively. RESULTS: miR-302c-3p decreased not only HBV replication but also production of HBsAg. Pregenomic RNA and HBsAg mRNA concentrations decreased in the cells treated with miR-302c-3p. Interestingly, the amount of cccDNA was significantly reduced in the miR-302c-3p-treated cells, in association with disappearance of the HBV core protein. An RNA immunoprecipitation assay showed that miR-302c-3p decreased the binding of the HBV polymerase to the pregenomic RNA by hybridising with the ε-loop region. A number of host genes were downregulated in miR-302c-3p-treated cells, including BMPR2 and HNF4A. Knockdown of these two genes by corresponding siRNAs also suppressed HBV replication and HBsAg secretion. The antiviral effect of miR-302c-3p was also observed in HBV transgenic mice. CONCLUSION: miR-302c-3p had anti-HBV activity, in vitro and in vivo, via several mechanisms.
  • MicroRNA hsa-miR-324-5p Suppresses H5N1 Virus Replication by Targeting the Viral PB1 and Host CUEDC2.
    Kumar A; Kumar A; Ingle H; Kumar S; Mishra R; Verma MK; Biswas D; Kumar NS; Mishra A; Raut AA; Takaoka A; Kumar H
    J Virol., 92, 19, e01057, Sep. 2018
  • Cancer cells deliver a suppressive cargo.
    Takaoka A
    Nat Immunol., 19, 3, 207, 208, Mar. 2018
  • Aureobasidium pullulans produced β-glucan is effective to enhance Kurosengoku soybean extract induced Thrombospondin-1 expression
    Daisuke Muramatsu; Mitsuyasu Okabe; Akinori Takaoka; Hiroshi Kida; Atsushi Iwai
    Scientific Reports, 7, 1, 2831, Nature Publishing Group, 01 Dec. 2017
    English, Scientific journal
  • Essential role of HCMV deubiquitinase in promoting oncogenesis by targeting anti-viral innate immune signaling pathways
    Puja Kumari; Irene Saha; Athira Narayanan; Sathish Narayanan; Akinori Takaoka; Nachimuthu Senthil Kumar; Prafullakumar Tailor; Himanshu Kumar
    CELL DEATH & DISEASE, 8, 10, e3078, Oct. 2017, [Peer-reviewed]
    English, Scientific journal
  • Involvement of Zizimin2/3 in the age-related defect of peritoneal B-1a cells as a source of anti-bacterial IgM
    Akihiko Sakamoto; Takenori Matsuda; Koichiro Kawaguchi; Akinori Takaoka; Mitsuo Maruyama
    International Immunology, 29, 9, 431, 438, Oxford University Press, 2017, [Peer-reviewed]
    English, Scientific journal
  • TRIM25 Enhances the Antiviral Action of Zinc-Finger Antiviral Protein (ZAP)
    Melody M. H. Li; Zerlina Lau; Pamela Cheung; Eduardo G. Aguilar; William M. Schneider; Leonia Bozzacco; Henrik Molina; Eugen Buehler; Akinori Takaoka; Charles M. Rice; Dan P. Felsenfeld; Margaret R. MacDonald
    PLOS PATHOGENS, 13, 1, e1006145, Jan. 2017, [Peer-reviewed]
    English, Scientific journal
  • Constitutive aryl hydrocarbon receptor signaling constrains type I interferon-mediated antiviral innate defense
    Taisho Yamada; Hiromasa Horimoto; Takeshi Kameyama; Sumio Hayakawa; Hiroaki Yamato; Masayoshi Dazai; Ayato Takada; Hiroshi Kida; Debbie Bott; Angela C. Zhou; David Hutin; Tania H. Watts; Masahiro Asaka; Jason Matthews; Akinori Takaoka
    NATURE IMMUNOLOGY, 17, 6, 687, +, Jun. 2016, [Peer-reviewed]
    English, Scientific journal
  • Helicobacter pylori induces IL-1 beta protein through the inflammasome activation in differentiated macrophagic cells
    Shoichiro Kameoka; Takeshi Kameyama; Takaya Hayashi; Seiichi Sato; Naomi Ohnishi; Takeru Hayashi; Naoko Murata-Kamiya; Hideaki Higashi; Masanori Hatakeyama; Akinori Takaoka
    BIOMEDICAL RESEARCH-TOKYO, 37, 1, 21, 27, 2016, [Peer-reviewed]
    English, Scientific journal
  • Pattern recognition receptor-mediated sensing mechanism during hepatitis virus infection
    Akinori Takaoka; Amiko Masuya; Naoya Katsuyama
    Seikagaku, 88, 3, 419, 424, Japanese Biochemical Society, 2016
    Japanese
  • The microRNA miR-485 targets host and influenza virus transcripts to regulate antiviral immunity and restrict viral replication
    Harshad Ingle; Sushil Kumar; Ashwin Ashok Raut; Anamika Mishra; Diwakar Dattatraya Kulkarni; Takeshi Kameyama; Akinori Takaoka; Shizuo Akira; Himanshu Kumar
    Science Signaling, 8, 406, ra126, American Association for the Advancement of Science, 08 Dec. 2015, [Peer-reviewed]
    English, Scientific journal
  • Superoxide Dismutase 1 Protects Hepatocytes from Type I Interferon-Driven Oxidative Damage
    Anannya Bhattacharya; Ahmed N. Hegazy; Nikolaus Deigendesch; Lindsay Kosack; Jovana Cupovic; Richard K. Kandasamy; Andrea Hildebrandt; Doron Merkler; Anja A. Kuehl; Bojan Vilagos; Christopher Schliehe; Isabel Panse; Kseniya Khamina; Hatoon Baazim; Isabelle Arnold; Lukas Flatz; Haifeng C. Xu; Philipp A. Lang; Alan Aderem; Akinori Takaoka; Giulio Superti-Furga; Jacques Colinge; Burkhard Ludewig; Max Loehning; Andreas Bergthaler
    IMMUNITY, 43, 5, 974, 986, Nov. 2015, [Peer-reviewed]
    English, Scientific journal
  • IPS-1 differentially induces TRAIL, BCL2, BIRC3 and PRKCE in type i interferons-dependent and-independent anticancer activity
    S. Kumar; H. Ingle; S. Mishra; R. S. Mahla; A. Kumar; T. Kawai; S. Akira; A. Takaoka; A. A. Raut; H. Kumar
    Cell Death and Disease, 6, 5, e1758, Nature Publishing Group, 01 May 2015, [Peer-reviewed]
    English, Scientific journal
  • Stimulation of Macrophages with the beta-Glucan Produced by Aureobasidium pullulans Promotes the Secretion of Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL)
    Koji Kawata; Atsushi Iwai; Daisuke Muramatsu; Shiho Aoki; Hirofumi Uchiyama; Mitsuyasu Okabe; Sumio Hayakawa; Akinori Takaoka; Tadaaki Miyazaki
    PLOS ONE, 10, 4, e0124809, Apr. 2015, [Peer-reviewed]
    English, Scientific journal
  • The immunosenescence-related gene Zizimin2 is associated with early bone marrow B cell development and marginal zone B cell formation
    Takenori Matsuda; Shougo Yanase; Akinori Takaoka; Mitsuo Maruyama
    IMMUNITY & AGEING, 12, 1, Feb. 2015, [Peer-reviewed]
    English, Scientific journal
  • The RNA Sensor RIG-I Dually Functions as an Innate Sensor and Direct Antiviral Factor for Hepatitis B Virus
    Seiichi Sato; Kai Li; Takeshi Kameyama; Takaya Hayashi; Yuji Ishida; Shuko Murakami; Tsunamasa Watanabe; Sayuki Iijima; Yu Sakurai; Koichi Watashi; Susumu Tsutsumi; Yusuke Sato; Hidetaka Akita; Takaji Wakita; Charles M. Rice; Hideyoshi Harashima; Michinori Kohara; Yasuhito Tanaka; Akinori Takaoka
    IMMUNITY, 42, 1, 123, 132, Jan. 2015, [Peer-reviewed]
    English, Scientific journal
  • Tumor-α9β1 integrin-mediated signaling induces breast cancer growth and lymphatic metastasis via the recruitment of cancer-associated fibroblasts.
    Daichi Ota; Masashi Kanayama; Yutaka Matsui; Koyu Ito; Naoyoshi Maeda; Goro Kutomi; Koichi Hirata; Toshihiko Torigoe; Noriyuki Sato; Akinori Takaoka; Ann F Chambers; Junko Morimoto; Toshimitsu Uede
    Journal of molecular medicine (Berlin, Germany), 92, 12, 1271, 81, Dec. 2014, [Peer-reviewed], [International Magazine]
    English, UNLABELLED: Tumor-derived matricellular proteins such as osteopontin (OPN) and tenascin-C (TN-C) have been implicated in tumor growth and metastasis. However, the molecular basis of how these proteins contribute to tumor progression remains to be elucidated. Importantly, these matricellular proteins are known to interact with α9β1 integrin. Therefore, we hypothesized that tumor-derived α9β1 integrin may contribute to tumor progression. To clarify the roles of α9β1 integrin in tumor growth and lymphatic metastasis, we used an inhibitory anti-human α9β1 integrin antibody (anti-hα9β1 antibody) and a α9β1 integrin-positive human breast cancer cell line, MDA-MB-231 luc-D3H2LN (D3H2LN), in vitro functional assays, and an in vivo orthotopic xenotransplantation model. In this study, we demonstrated that tumor, but not host α9β1 integrin, contributes to tumor growth, lymphatic metastasis, recruitment of cancer-associated fibroblasts (CAFs), and host-derived OPN production. We also found that CAFs contributed to tumor growth, lymphatic metastasis, and host-derived OPN levels. Consistent with those findings, tumor volume was well-correlated with numbers of CAFs and levels of host-derived OPN. Furthermore, it was shown that the inoculation of D3H2LN cells into mammary fat pads with mouse embryonic fibroblasts (MEFs), obtained from wild type, but not OPN knock-out mice, resulted in enhancement of tumor growth, thus indicating that CAF-derived OPN enhanced tumor growth. These results suggested that tumor α9β1-mediated signaling plays a pivotal role in generating unique primary tumor tissue microenvironments, which favor lymphatic metastasis and tumor growth. KEY MESSAGES: Tumor α9β1 integrin promotes lymphatic metastasis through enhancing invasion. Tumor α9β1 integrin promotes tumor growth through CAFs. Tumor α9β1 integrin enhances the recruitment of CAFs into the primary tumor. Tumor cells induce the production of OPN by CAFs in the primary tumor. CAF-derived OPN promotes tumor growth.
  • Integrin α9 on lymphatic endothelial cells regulates lymphocyte egress.
    Koyu Ito; Junko Morimoto; Akio Kihara; Yutaka Matsui; Daisuke Kurotaki; Masashi Kanayama; Szandor Simmons; Masaru Ishii; Dean Sheppard; Akinori Takaoka; Toshimitsu Uede
    Proceedings of the National Academy of Sciences of the United States of America, 111, 8, 3080, 5, 25 Feb. 2014, [Peer-reviewed], [International Magazine]
    English, Scientific journal, Sphingosine 1-phosphate (S1P) plays a role in lymphocyte egress from lymphoid organs. However, it remains unclear how S1P production and secretion are regulated. We show that under inflammatory conditions, α9 integrin, which is closely associated with activated β1 integrin, and its ligand, tenascin-C, colocalize on medullary and cortical sinuses of draining lymph nodes (dLNs), which is a gate for lymphocyte exit, and that inhibition of lymphocyte egress is evident by blockade of α9 integrin-mediated signaling at dLNs. Based on in vitro analysis using lymphatic endothelial cells obtained from mice embryos, we suggested the possibility that stimulation of lymphatic endothelial cells by tenascin-C enhances S1P secretion in an α9 integrin-dependent manner without affecting S1P synthesis and/or degradation. Blockade of α9 integrin-mediated signaling reduced lymphocyte egress from dLNs in several models, including experimental autoimmune encephalomyelitis, where it improved clinical scores and pathology. Therefore, manipulating α9 integrin function may offer a therapeutic strategy for treating various inflammatory disorders.
  • Characterization of innate immune signalings stimulated by ligands for pattern recognition receptors.
    Kameyama T; Takaoka A
    Methods in molecular biology (Clifton, N.J.), 1142, 19, 32, 2014, [Peer-reviewed]
  • Targeted Induction of Interferon-lambda in Humanized Chimeric Mouse Liver Abrogates Hepatotropic Virus Infection
    Shin-ichiro Nakagawa; Yuichi Hirata; Takeshi Kameyama; Yuko Tokunaga; Yasumasa Nishito; Kazuko Hirabayashi; Junichi Yano; Takahiro Ochiya; Chise Tateno; Yasuhito Tanaka; Masashi Mizokami; Kyoko Tsukiyama-Kohara; Kazuaki Inoue; Makoto Yoshiba; Akinori Takaoka; Michinori Kohara
    PLOS ONE, 8, 3, e59611., Mar. 2013, [Peer-reviewed]
    English, Scientific journal
  • Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1
    Shigeki Chiba; Muhammad Baghdadi; Hisaya Akiba; Hironori Yoshiyama; Ichiro Kinoshita; Hirotoshi Dosaka-Akita; Yoichiro Fujioka; Yusuke Ohba; Jacob V. Gorman; John D. Colgan; Mitsuomi Hirashima; Toshimitsu Uede; Akinori Takaoka; Hideo Yagita; Masahisa Jinushi
    NATURE IMMUNOLOGY, 13, 9, 832, 842, Sep. 2012
    English, Scientific journal
  • ATM-mediated DNA damage signals mediate immune escape through integrin-αvβ3-dependent mechanisms.
    Masahisa Jinushi; Shigeki Chiba; Muhammad Baghdadi; Ichiro Kinoshita; Hirotoshi Dosaka-Akita; Koyu Ito; Hironori Yoshiyama; Hideo Yagita; Toshimitsu Uede; Akinori Takaoka
    Cancer research, 72, 1, 56, 65, 01 Jan. 2012, [International Magazine]
    English, Although the tumor microenvironment plays a critical role in tumor progression and metastasis, the relationship between chemotherapy resistance and modulation of the tumor microenvironment remains unclear. Here, we report a novel mechanism showing how constitutive DNA damage signals in therapy-resistant tumor cells suppress antitumor immunity in an integrin-αvβ3-dependent manner. Integrin-αvβ3 was upregulated on various therapy-resistant tumor cells through chronic activation of ATM/Chk2-and NFκB-mediated pathways. Inhibiting tumor-specific expression of integrin-αvβ3 improved therapeutic responses to anticancer drugs by stimulating endogenous host immune systems. Mechanistic investigations revealed that tumor-specific integrin-αvβ3 expression targeted dendritic cells, facilitating their ability to phagocytose viable therapy-resistant tumor cells and thereby impaired their ability to cross-prime antigen-specific T lymphocytes. Together, our results clarify the detrimental effects of constitutive DNA damage signals to chemosensitivity and antitumor immunity. Furthermore, these findings suggest that integrin-αvβ3 targeting may benefit patients' refractory to current anticancer regimens by defeating DNA damage signaling-induced immune escape.
  • Dendritic cell-derived TIM-3 is a universal repressor of nucleic acids-mediated antitumor innate immune responses.
    Chiba S; Baghdadi M; Akiba H; Kinoshita I; Yoshiyama H; Hirashima M; Dosaka-Akita H; Uede T; Takaoka A; Yagita H; Jinushi M
    Nat Immunol, 13, 9, 832, 842, 2012
  • Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells
    Masahisa Jinushi; Shigeki Chiba; Hironori Yoshiyama; Kenkichi Masutomi; Ichiro Kinoshita; Hirotoshi Dosaka-Akita; Hideo Yagita; Akinori Takaoka; Hideaki Tahara
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 108, 30, 12425, 12430, Jul. 2011
    English, Scientific journal
  • Interferon-alpha/beta and Anti-Fibroblast Growth Factor Receptor 1 Monoclonal Antibody Suppress Hepatic Cancer Cells In Vitro and In Vivo
    Shigeru Sasaki; Tadao Ishida; Minoru Toyota; Akinobu Ota; Hiromu Suzuki; Akinori Takaoka; Hiroshi Yasui; Hiroyuki Yamamoto; Hideyasu Takagi; Masahiro Maeda; Tsutomu Seito; Masayuki Tsujisaki; Yasuhisa Shinomura; Kohzoh Imai
    PLOS ONE, 6, 5, e19618, May 2011
    English, Scientific journal
  • IRF3 regulates cardiac fibrosis but not hypertrophy in mice during angiotensin II-induced hypertension
    Kensuke Tsushima; Tomoko Osawa; Hideyuki Yanai; Akira Nakajima; Akinori Takaoka; Ichiro Manabe; Yusuke Ohba; Yasushi Imai; Tadatsugu Taniguchi; Ryozo Nagai
    FASEB JOURNAL, 25, 5, 1531, 1543, May 2011
    English, Scientific journal
  • ZAPS is a potent stimulator of signaling mediated by the RNA helicase RIG-I during antiviral responses
    Sumio Hayakawa; Souichi Shiratori; Hiroaki Yamato; Takeshi Kameyama; Chihiro Kitatsuji; Fumi Kashigi; Showhey Goto; Shoichiro Kameoka; Daisuke Fujikura; Taisho Yamada; Tatsuaki Mizutani; Mika Kazumata; Maiko Sato; Junji Tanaka; Masahiro Asaka; Yusuke Ohba; Tadaaki Miyazaki; Masahiro Imamura; Akinori Takaoka
    NATURE IMMUNOLOGY, 12, 1, 37, U56, Jan. 2011
    English, Scientific journal
  • 抗ウイルス応答のためのRIG-1を介するシグナルを強く刺激する分子の同定(Identification of a potent stimulator of RIG-I mediated signaling for antiviral response)
    北辻 千展; 早川 清雄; 白鳥 聡一; 大和 弘明; 亀山 武志; 樫木 芙美; 後藤 翔平; 亀岡 章一郎; 大場 雄介; 宮崎 忠昭; 高岡 晃教
    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集, 83回・33回, 2T11, 11, (公社)日本生化学会, Dec. 2010
    English
  • Critical role for constitutive type I interferon signaling in the prevention of cellular transformation
    Hui-min Chen; Nobuyuki Tanaka; Yukiko Mitani; Eri Oda; Hiroaki Nozawa; Jian-zhong Chen; Hideyuki Yanai; Hideo Negishi; Myoung Kwon Choi; Toshiroh Iwasaki; Hiroyuki Yamamoto; Tadatsugu Taniguchi; Akinori Takaoka
    CANCER SCIENCE, 100, 3, 449, 456, Mar. 2009
    English, Scientific journal
  • DNA sensors in innate immune system
    TAKAOKA Akinori; SHINOHARA Shigeki
    Uirusu, 58, 1, 37, 46, The Japanese Society for Virology, 22 Jun. 2008
    Japanese, Microbial sensing mediated by pattern recognition receptors (PRRs) is the first key step to trigger innate immune responses, represented by the induction of type I interferons (IFNs), proinflammatory cytokines and chemokines. This innate signaling elicits an efficient activation of more specific responses in adaptive immunity. Such coordinated responses in the two systems are essential for the optimal elimination of invading microbes. Despite a major advance in our understanding of RNA sensors, TLR9 remained the only known sensor of DNA. On the other hand, there has been accumulating evidence supporting the existence of TLR9-independent DNA recognition mechanism. In this regard, DAI (also termed as DLM-1/ZBP1), the first sensor of cytosolic DNA, has recently been identified with its activation of IFN-regulatory factors(IRFs) and NF-κB transcriptional factors. Several recent papers suggest the involvement of an additional cytosolic DNA sensor(s). There is also a recent report that cytosolic microbial and host DNA can trigger pro-inflammatory responses via the TLR- and IRF-indepnedent pathway mediated by the inflammasome, which is consisted of NLR family members together with the adaptor protein ASC and caspase-1. In addition, evidence has been provided that host- and virus-derived proteins, which contain DNA-binding motifs (Zα and/or Zβ) similar to those of DAI(DLM-1/ZBP1), negatively regulates the immune response that is activated by cytosolic DNA. Thus, these recent findings reveal the complex DNA-sensing mechanism for triggering the activation of innate immunity, and the breakdown of this sensing mechanism may lead to autoimmune abnormalities.
  • Regulation of innate immune responses by DAI (DLM-1/ZBP1) and other DNA-sensing molecules
    ZhiChao Wang; Myoung Kwon Choi; Tatsuma Ban; Hideyuki Yanai; Hideo Negishi; Yan Lu; Tomohiko Tamura; Akinori Takaoka; Kazuko Nishikura; Tadatsugu Taniguchi
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 105, 14, 5477, 5482, Apr. 2008
    English, Scientific journal
  • Cytosolic DNA recognition for triggering innate immune responses
    Akinori Takaoka; Tadatsudu Taniguchi
    ADVANCED DRUG DELIVERY REVIEWS, 60, 7, 847, 857, Apr. 2008
    English
  • Interferon regulatory factor family of transcription factors and regulation of oncogenesis
    Akinori Takaoka; Tomohiko Tamura; Tadatsugu Taniguchi
    CANCER SCIENCE, 99, 3, 467, 478, Mar. 2008
    English
  • DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response
    Akinori Takaoka; ZhiChao Wang; Myoung Kwon Choi; Hideyuki Yanai; Hideo Negishi; Tatsuma Ban; Yan Lu; Makoto Miyagishi; Tatsuhiko Kodama; Kenya Honda; Yusuke Ohba; Tadatsugu Taniguchi
    NATURE, 448, 7152, 501, U14, Jul. 2007
    English, Scientific journal
  • Role of IFN regulatory factor 5 transcription factor in antiviral immunity and tumor suppression
    Hideyuki Yanai; Hui-min Chen; Takayuki Inuzuka; Seiji Kondo; Tak W. Mak; Akinori Takaoka; Kenya Honda; Tadatsugu Taniguchi
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 104, 9, 3402, 3407, Feb. 2007
    English, Scientific journal
  • Differential contribution of Puma and Noxa in dual regulation of p53-mediated apoptotic pathways
    Tsukasa Shibue; Saori Suzuki; Hideaki Okamoto; Hiroki Yoshida; Yusuke Ohba; Akinori Takaoka; Tadatsugu Taniguchi
    EMBO Journal, 25, 20, 4952, 4962, 18 Oct. 2006, [Peer-reviewed]
    English, Scientific journal
  • Comparing antibody and small-molecule therapies for cancer
    Kohzoh Imai; Akinori Takaoka
    NATURE REVIEWS CANCER, 6, 9, 714, 727, Sep. 2006
    English
  • Type I Inteferon Gene Induction by the Interferon Regulatory Factor Family of Transcription Factors
    Kenya Honda; Akinori Takaoka; Tadatsugu Taniguchi
    Immunity, 25, 3, 349, 360, Sep. 2006, [Peer-reviewed]
    English
  • Interplay between interferon and other cytokine systems in bone metabolism
    H Takayanagi; K Sato; A Takaoka; T Taniguchi
    IMMUNOLOGICAL REVIEWS, 208, 181, 193, Dec. 2005, [Peer-reviewed]
    English
  • IRF family transcription factors in type I interferon induction
    Hideyuki Yanai; Tatsuaki Mizutani; Takayuki Inuzuka; Kenya Honda; Akinori Takaoka; Tadatsugu Taniguchi
    International Congress Series, 1285, 104, 113, Nov. 2005, [Peer-reviewed], [Invited]
    English, Scientific journal
  • Regulation of the type I IFN induction: A current view
    Kenya Honda; Hideyuki Yanai; Akinori Takaoka; Tadatsugu Taniguchi
    International Immunology, 17, 11, 1367, 1378, Nov. 2005, [Peer-reviewed]
    English
  • Negative regulation of Toll-like-receptor signaling by IRF-4
    Hideo Negishi; Yusuke Ohba; Hideyuki Yanai; Akinori Takaoka; Kiri Honma; Katsuyuki Yui; Toshifumi Matsuyama; Tadatsugu Taniguchi; Kenya Honda
    Proceedings of the National Academy of Sciences of the United States of America, 102, 44, 15989, 15994, 01 Nov. 2005, [Peer-reviewed]
    English, Scientific journal
  • Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction
    K Honda; Y Ohba; H Yanai; H Negishi; T Mizutani; A Takaoka; C Taya; T Taniguchi
    NATURE, 434, 7036, 1035, 1040, Apr. 2005
    English, Scientific journal
  • IRF-7 is the master regulator of type-I interferon-dependent immune responses
    K Honda; H Yanai; H Negishi; M Asagiri; M Sato; T Mizutani; N Shimada; Y Ohba; A Takaoka; N Yoshida; T Taniguchi
    NATURE, 434, 7034, 772, 777, Apr. 2005
    English, Scientific journal
  • Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors
    A Takaoka; H Yanai; S Kondo; G Duncan; H Negishi; T Mizutani; S Kano; K Honda; Y Ohba; TW Mak; T Taniguchi
    NATURE, 434, 7030, 243, 249, Mar. 2005
    English, Scientific journal
  • Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling
    Kenya Honda; Hideyuki Yanai; Tatsuaki Mizutani; Hideo Negishi; Naoya Shimada; Nobutaka Suzuki; Yusuke Ohba; Akinori Takaoka; Wen-Chen Yeh; Tadatsugu Taniguchi
    Proceedings of the National Academy of Sciences of the United States of America, 101, 43, 15416, 15421, 26 Oct. 2004, [Peer-reviewed]
    English, Scientific journal
  • Selective contribution of IFN-α/β signaling to the maturation of dendritic cells induced by double-stranded RNA or viral infection
    Kenya Honda; Shinya Sakaguchi; Chigusa Nakajima; Ai Watanabe; Hideyuki Yanai; Misako Matsumoto; Toshiaki Ohteki; Tsuneyasu Kaisho; Akinori Takaoka; Shizuo Akira; Tsukasa Seya; Tadatsugu Taniguchi
    Proceedings of the National Academy of Sciences of the United States of America, 100, 19, 10872, 10877, 16 Sep. 2003, [Peer-reviewed]
    English, Scientific journal
  • Integral role of Noxa in p53-mediated apoptotic response
    T Shibue; K Takeda; E Oda; H Tanaka; H Murasawa; A Takaoka; Y Morishita; S Akira; T Taniguchi; N Tanaka
    GENES & DEVELOPMENT, 17, 18, 2233, 2238, Sep. 2003, [Peer-reviewed]
    English, Scientific journal
  • Essential role of IRF-3 in lipopolysaccharide-induced interferon-β gene expression and endotoxin shock
    Shinya Sakaguchi; Hideo Negishi; Masataka Asagiri; Chigusa Nakajima; Tatsuaki Mizutani; Akinori Takaoka; Kenya Honda; Tadatsugu Taniguchi
    Biochemical and Biophysical Research Communications, 306, 4, 860, 866, Academic Press Inc., 11 Jul. 2003, [Peer-reviewed]
    English, Scientific journal
  • Integration of interferon-alpha/beta signalling to p53 responses in tumour suppression and antiviral defence
    A Takaoka; S Hayakawa; H Yanai; D Stoiber; H Negishi; H Kikuchi; S Sasaki; K Imai; T Shibue; K Honda; T Taniguchi
    NATURE, 424, 6948, 516, 523, Jul. 2003
    English, Scientific journal
  • New aspects of IFN-α/β signalling in immunity, oncogenesis and bone metabolism
    Akinori Takaoka; Tadatsugu Taniguchi
    Cancer Science, 94, 5, 405, 411, Japanese Cancer Association, 01 May 2003, [Peer-reviewed]
    English
  • 免疫応答と発がん制御におけるシグナル伝達と遺伝子発現ネットワーク
    谷口 維紹; 高岡 晃教; 本田 賢也; 高柳 広
    日本臨床免疫学会会誌 = Japanese journal of clinical immunology, 25, 5, 375, 375, 日本臨床免疫学会, 31 Oct. 2002
    Japanese
  • The interferon-α/β system in antiviral responses: A multimodal machinery of gene regulation by the IRF family of transcription factors
    Tadatsugu Taniguchi; Akinori Takaoka
    Current Opinion in Immunology, 14, 1, 111, 116, Elsevier Ltd, 01 Feb. 2002, [Peer-reviewed]
    English
  • A critical role for mouse CXC chemokine(s) in pulmonary neutrophilia during Th type 1-dependent airway inflammation
    A. Takaoka; Y. Tanaka; T. Tsuji; T. Jinushi; A. Hoshino; Y. Asakura; Y. Mita; K. Watanabe; S. Nakaike; Y. Togashi; T. Koda; K. Matsushima; T. Nishimura
    Journal of Immunology, 167, 4, 2349, 2353, American Association of Immunologists, 15 Aug. 2001, [Peer-reviewed]
    English, Scientific journal
  • Cross talk of the interferon-alpha/beta signalling complex with gp130 for effective interleukin-6 signalling
    Y Mitani; A Takaoka; SH Kim; Y Kato; T Yokochi; N Tanaka; T Taniguchi
    GENES TO CELLS, 6, 7, 631, 640, Jul. 2001, [Peer-reviewed]
    English, Scientific journal
  • A weak signal for strong responses: Interferon-alpha/beta revisited
    T Taniguchi; A Takaoka
    NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2, 5, 378, 386, May 2001
    English
  • IRF family of transcription factors as regulators of host defense
    T Taniguchi; K Ogasawara; A Takaoka; N Tanaka
    ANNUAL REVIEW OF IMMUNOLOGY, 19, 623, 655, 2001
    English
  • Constitutive IFN-α/β signal for efficient IFN-α/β gene induction by virus
    Naoki Hata; Mitsuharu Sato; Akinori Takaoka; Masataka Asagiri; Nobuyuki Tanaka; Tadatsugu Taniguchi
    Biochemical and Biophysical Research Communications, 285, 2, 518, 525, 2001, [Peer-reviewed]
    English, Scientific journal
  • T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma
    H Takayanagi; K Ogasawara; S Hida; T Chiba; S Murata; K Sato; A Takaoka; T Yokochi; H Oda; K Tanaka; K Nakamura; T Taniguchi
    NATURE, 408, 6812, 600, 605, Nov. 2000, [Peer-reviewed]
    English, Scientific journal
  • Differential requirement of the cytoplasmic subregions of gamma c chain in T cell development and function
    S Tsujino; JP Di Santo; A Takaoka; TL McKernan; S Noguchi; C Taya; H Yonekawa; T Saito; T Taniguchi; H Fujii
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 97, 19, 10514, 10519, Sep. 2000
    English, Scientific journal
  • Cross talk between interferon-gamma and -alpha/beta signaling components in caveolar membrane domains
    A Takaoka; Y Mitani; H Suemori; M Sato; T Yokochi; S Noguchi; N Tanaka; T Taniguchi
    SCIENCE, 288, 5475, 2357, 2360, Jun. 2000
    English, Scientific journal
  • Protein tyrosine kinase Pyk2 mediates the Jak-dependent activation of MAPK and Stat1 in IFN-γ, but not IFN-α, signaling
    Akinori Takaoka; Nobuyuki Tanaka; Yukiko Mitani; Tadaaki Miyazaki; Hodaka Fujii; Mitsuharu Sato; Pavel Kovarik; Thomas Decker; Joseph Schlessinger; Tadatsugu Taniguchi
    EMBO Journal, 18, 9, 2480, 2488, 04 May 1999, [Peer-reviewed]
    English, Scientific journal
  • Transcription factor IRF-1 and its family members in the regulation of host defense
    T. Taniguchi; N. Tanaka; K. Ogasawara; S. Taki; M. Sato; A. Takaoka
    Cold Spring Harbor Symposia on Quantitative Biology, 64, 465, 472, Cold Spring Harbor Laboratory Press, 1999, [Peer-reviewed]
    English, International conference proceedings
  • Pyk2 is a downstream mediator of the IL-2 receptor-coupled Jak signaling pathway
    Tadaaki Miyazaki; Akinori Takaoka; Leonor Nogueira; Ivan Dikic; Hodaka Fujii; Shiho Tsujino; Yukiko Mitani; Michiyuki Maeda; Joseph Schlessinger; Tadatsugu Taniguchi
    Genes and Development, 12, 6, 770, 775, Cold Spring Harbor Laboratory Press, 15 Mar. 1998, [Peer-reviewed]
    English, Scientific journal
  • Gastric antral vascular ectasia causing severe anemia
    Mlnoru Toyota; Yuji Hlnoda; Naoaki Nakagawa; Yoshiaki Arimura; Shigeru Tokuchi; Akinori Takaoka; Shingo Kitagawa; Toshihiro Usuki; Tsuyoshi Yabana; Akira Yachi; Kohzoh Imai
    Journal of Gastroenterology, 31, 5, 710, 713, 1996, [Peer-reviewed]
    English, Scientific journal
■ Other Activities and Achievements
■ Lectures, oral presentations, etc.
  • Direct and indirect roles of RIG-I for antiviral defense against hepatitis B virus in human hepatocytes
    TAKAOKA Akinori
    International Conference on Antimicrobial Research, Oct. 2014, English, Oral presentation
    [International presentation]
  • Role of the cytoplasmic RNA sensor RIG-I in innate immune defense against hepatitis B virus infection
    TAKAOKA Akinori
    11th International Conference on Innate Immunity, Jun. 2014, English, Oral presentation
    [International presentation]
  • ZAPS acts as a key factor of RIG-I-mediated activation of innate immune responses during influenza virus
    TAKAOKA Akinori
    2nd International Conference on Clinical & Cellular Immunology, Oct. 2013, English, Oral presentation
    [International presentation]
  • Innate immune signaling networks during host-microbe interaction
    TAKAOKA Akinori
    CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 01 Jul. 2013, English, Invited oral presentation
    [International presentation]
  • Nucleic acid sensors for detecting viral infection
    髙岡 晃教
    IEIIS2012 Homeostatic Inflammation Symposium, 23 Oct. 2012
  • Roles of ZAPS as an antiviral regulator in innate immunity
    髙岡 晃教
    2nd CSI/JSI/KAI Joint Symposium on Immunology (2011日中韓 合同 免疫シンポジウム), 04 Dec. 2011
  • Identification of a novel regulator of the innate signaling activated by virus-derived nucleic acids
    髙岡 晃教
    2010 annual meeting of the french society for immunology, 25 Nov. 2010
  • Activation of Innate Immune Response Mediated by DNA-triggered Danger Signals
    髙岡 晃教
    The 36th Congress of the International Society of Oncology & BioMarkers, 06 Oct. 2008
■ Syllabus
  • 医学研究演習, 2024年, 学士課程, 医学部
  • 大学院共通授業科目（一般科目）：自然科学・応用科学, 2024年, 修士課程, 大学院共通科目
  • 生物化学Ａ（Ⅱ）, 2024年, 修士課程, 総合化学院
  • 基礎生物化学特論, 2024年, 修士課程, 総合化学院
  • 先端総合化学特論Ⅱ, 2024年, 博士後期課程, 総合化学院
  • 一般教育演習(ﾌﾚｯｼｭﾏﾝｾﾐﾅｰ), 2024年, 学士課程, 全学教育
  • 一般教育演習(ﾌﾚｯｼｭﾏﾝｾﾐﾅｰ), 2024年, 学士課程, 全学教育
  • 分子生理学, 2024年, 学士課程, 理学部
■ Affiliated academic society
  • 日本ウイルス学会
  • 日本免疫学会
  • International Society for Interferon and Cytokine Research
  • International Cytokine Society
  • 日本分子生物学会
  • 日本癌学会
  • 北海道医学会
  • 北海道癌談話会
  • 日本生化学会
  • がん分子標的治研究会
  • 日本インターフェロン・サイトカイン学会
■ Research Themes
  • lncRNAからエンコードされる新しい抗ウイルスサイトカインの同定と性状解析
    科学研究費助成事業
    28 Jun. 2024 - 31 Mar. 2027
    高岡 晃教; 久米田 博之; 佐藤 精一
    日本学術振興会, 挑戦的研究(萌芽), 北海道大学, 24K22043
  • Intrinsic immunityに着目した新しい抗ウイルス防御機構の探索
    科学研究費助成事業
    01 Apr. 2022 - 31 Mar. 2027
    高岡 晃教
    日本学術振興会, 基盤研究(A), 北海道大学, 22H00447
  • Research on the immune system in uninfected cells that defines the immune response during viral infection
    Grants-in-Aid for Scientific Research
    01 Apr. 2018 - 31 Mar. 2021
    Kameyama Takeshi
    Interferons (IFNs) are the main cytokines for the innate immune response against viral infection. It is known that IFNs are constitutively induced at very low levels in the absence of viral infection. These constitutively induced IFNs and their signals are essential for the rapid and robust induction of IFN induction after viral infection and for the suppression of carcinogenesis. However, the mechanism of this constitutive IFN induction and its regulation remains unclear. In this study, we found that the constitutive IFNs are induced through an intracellular RNA sensor-dependent recognition of endogenous RNAs and the downstream signaling pathway. Furthermore, we found several regulatory factors that regulate cytosolic nucleic acid-mediated innate immune responses. These results identified a novel regulatory mechanism that controls constitutively induced IFNs, which may provide a novel prophylactic target for viral control and suppression of carcinogenesis.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Kobe University, 18K07162
  • The molecular mechanism of cancer specific cell death induction via novel innate immune signaling
    Grants-in-Aid for Scientific Research
    30 Jun. 2017 - 31 Mar. 2020
    Takaoka Akinori
    We have been working on the study of innate signaling via pattern recognition mediated receptor for antiviral responses. In this study, we identified a novel innate signaling pathway via cytosolic RNA sensor RIG-I that activates cell death in cancer cells but not normal cells. This novel pathway is different from conventional pathway via MAVS/IPS-1 mediated IFN inducing pathway. Importantly, localization of a kinase protein is not only nucleus but also cytosol in cancer cells while the localization of this is only nucleus in normal cells. RIG-I in cancer cells activate this kinase and activates apoptosis in cancer cells. Based on our finding that a kinase is localized in cytosol of cancer cells, we propose a novel strategy to modulate ectopic protein for cancer therapy for cancer cells' death.
    Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Research (Pioneering), Hokkaido University, 17H06265
  • The novel post-transcriptional regulation mechanism of antiviral host defense
    Grants-in-Aid for Scientific Research
    01 Apr. 2013 - 31 Mar. 2018
    Takaoka Akinori
    Viral infection is one of the most critical problems for our health. Elucidation of host immune response against invading viruses is crucial for better understanding of the pathological processes and viral elimination to control viral infection. In this study, we reveal that PARP-13 shorter isoform (ZAPS) is involved in the post-transcriptional regulation of RSAD2 mRNA, one of the interferon-stimulated genes, which provide a novel host defense mechanism for elimination of viruses.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (A), Hokkaido University, 25253030
  • Activation of innate immune response by DNA from food
    Grants-in-Aid for Scientific Research
    01 Apr. 2014 - 31 Mar. 2017
    HAYAKAWA Sumio
    Food is recognized as one of the important factors which regulate human health such as immune response. It is known that vitamins, minerals and proteins are essential nutrients to build a healthy body. However, the role of food DNA on health is not clearly understood. So, we focused on the effect of food DNA on activation of innate immune signaling pathway mediated by PRRs. Here we show that a complex with the food DNA and short peptide, the only cathelicidin-derived antimicrobial peptide, activated innate immune response and functioned as a ligand of RIG-I in macrophage. We suggest that DNA from food could provide an application in therapy aimed at maintaining good health.
    Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Exploratory Research, Tokyo Medical and Dental University, 26560052
  • ヒトサイトメガロウイルス感染により活性化されるパターン認識受容体活性化機構の解析
    科学研究費助成事業
    01 Apr. 2013 - 31 Mar. 2015
    高岡 晃教
    健常人に広く潜伏感染しながら，特に臓器移植患者などで重篤な感染症を引き起こすDNAウイルスであるヒトサイトメガロウイルス（HCMV）は，日和見病原体として臨床では大きな問題となっているが，その自然免疫認識機構についてはまだ充分に明らかにされていない．そこで，HCMV感染を認識するPRRの同定を試みた結果，既知のDNAセンサー分子の中でIFI16がHCMV感染による自然免疫応答の活性化に関与することを示唆した．一方，IFI16に会合するHCMV由来のタンパク質として，構造タンパク質を見出した．このような結果を基に本研究では，HCMV感染によるIFI16経路の活性化の分子基盤を明らかにすることを目的とした．
    我々はHCMV感染時に活性化される自然免疫応答に既知の細胞質DNAセンサー分子IFI16が関与することを見出したが，HCMV由来のDNAはIFI16に認識されない可能性が示唆され，IFI16はHCMV由来の未知なる因子を認識している可能性が考えられた．一方，IFI16に会合することを新たに見出した，HCMV由来の構造タンパク質を細胞に過剰発現しただけでもIFI16依存的な自然免疫応答の活性化が認められた．さらに，この構造タンパク質をエンコードする遺伝子を欠損させたHCMVを用いた実験により，実際のHCMV感染時においてこの構造タンパク質が自然免疫応答を活性化することが確認された．一方，この構造タンパク質は酵素活性を有することが報告されていることから，この酵素活性のIFI16認識経路への影響についての検討を行った．その結果，この酵素活性はIFI16との会合に影響は与えなかったが，この構造タンパク質の酵素活性変異体を細胞に過剰発現させても自然免疫応答は認められなかった．このことは，この構造タンパク質の酵素活性にIFI16経路をONにする役割があることを示唆していると考えている．
    日本学術振興会, 新学術領域研究(研究領域提案型), 北海道大学, 25115502
  • Establishment of local and switchable innate immune activation by novel nucleic acid adjuvant
    Grants-in-Aid for Scientific Research
    01 Apr. 2013 - 31 Mar. 2015
    TAKAOKA Akinori; SATO Seiichi; KAMEYAMA Takeshi
    Adjuvant is an important component for effective vaccination and antitumor therapy. Establishment of local and switchable adjuvant is considered to be an efficient strategy to reduce side effects and efficiently activate innate immune responses. The purpose of this study is the establishment of a novel nucleic acid adjuvant that can trigger the activation of innate immune system in response to X-ray irradiation. In this study, type-C CpG ligands contained with cystamine-modified cytosine were used and showed its structural change by X-ray irradiation, albeit their low efficiency. These results showed these ligands could be a switchable activator and further investigation will be needed to improve their efficiency.
    Japan Society for the Promotion of Science, Grant-in-Aid for Challenging Exploratory Research, Hokkaido University, 25640084
  • ウイルスＲＮＡと宿主ＲＮＡによって調節される細胞機能制御のメカニズム
    科学研究費助成事業
    01 Apr. 2011 - 31 Mar. 2013
    高岡 晃教
    申請者がこれまで行ってきた自然免疫活性化機構に関する研究成果に基づき，RNAによって規定される生体防御の分子メカニズムや制御機構について，ウイルスRNAと宿主RNAの両方に視点を当てて解明することを目的とし，①直接作用(RNAの分解)と間接作用(RNA認識による免疫賦活)という2つの局面から追究すること,②宿主RNAを介する生体防御機構の制御について新しい仕組みを見出すことを目指した.
    ①について，申請者らが独自に同定した自然免疫調節因子ZAPSに着目し，その機能制御がDEAD box RNAヘリカーゼp72によって行われている可能性について調べた．その結果，ZAPSは細胞質においてp72と共局在しタンパク中央部分で会合すること，さらにRIG-IによるIFN誘導をZAPS依存的に正に制御することを見出した．そのメカニズムとしてRIG-I-ZAPS複合体をp72が活性化することが考えられた．②について，通常非感染細胞においてはごくわずかなI型IFNを構成的に発現することが知られているがその詳細については明らかになっていない．そこで本研究では，構成的なIFNの発現制御機構を調べた．その結果，構成的なIFNの発現は，RIG-I-ZAPSの経路に依存していることを見出した．さらにRIG-Iに結合する宿主RNAが存在し，このRNAは自然免疫系を活性化することを見出した．今後非感染時においてRIG-Iに結合するRNAを網羅的に解析し，構成的なIFNの発現制御機構を明らかにする予定である.
    このような本申請研究によって,ウイルスRNAと宿主RNAの2つの観点から，RNAプログラムによって制御される生体防御機構を明らかにしたことは，感染症においてRNA制御という新しい研究領域の推進や，疾患治療における新たな治療標的を創出することに大いに貢献することが考えられる.
    日本学術振興会, 新学術領域研究(研究領域提案型), 北海道大学, 23112701
  • The study of activation of innate immune response by dietary nucleic acids via oral mucosa
    Grants-in-Aid for Scientific Research
    2011 - 2013
    KAMEYAMA Takeshi; HAYAKAWA Sumio; ADACHI Yoshihiro Christopher; TAKAOKA Akinori; OKADA Kanako; TODA Haruka
    Diet contains various kinds of nutrient,, which keep us healthy. However the nutritional role of nucleic acids derived from diets is not clearly understood. The innate immunity system is an essential step as the front line of host defense. Although oral mucosa acts as powerful barriers, the importance of oral mucosa in innate immunity remains unclear. In this study, we demonstrate that DNA derived from vegetable activated innate immune response both in vitro and in vivo, which may provide the nutritional immunological role of dietary nucleic acids.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 23617001
  • Molecular mechanisms for the detection of microbes and cancer cells in innate immunity
    Grants-in-Aid for Scientific Research
    2008 - 2012
    TAKAOKA Akinori
    In this project, we tried to elucidate a regulatory mechanism for the activation of PRRs, particularly nucleic acid sensors, and the related signaling pathways, leading to the induction of cytokine/chemokine genes in innate immune responses for host defense against viral infection and cancer. First, we found that the poly(ADP-ribose) polymerase (PARP)-13 shorter isoform (ZAPS) critically functions as a potent stimulator of IFN responses in human cells mediated by RIG-I, through the physical association of ZAPS with RIG-I. Next, we revealed that ZAPS is a factor targeted by Influenza viral NS1 protein for viral innate immune evasion. In addition, we showed a role of PARP-7/TIPARP and PARP-12 as a possible negative regulator of RIG-I-meditated innate immune signalings. Furthermore, we also identified a candidate DNA sensor for human cytomegalovirus (HCMV). On the other hand, this project contributed to the research, wherein it has been shown a novel mechanism for the suppression of innate immune signalings mediated by tumor-derived DNA in tumor-infiltrating dendritic cells. These results may provide a therapeutic and preventive insight for the control of viral infection and cancer.
    Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists (S), Hokkaido University, 20679003
  • ウイルス感染におけるDNAを介する自然免疫応答の解明
    科学研究費助成事業
    2009 - 2010
    高岡 晃教
    本研究では、細胞質に存在するウイルス由来DNAを介して誘導される自然免疫応答の基盤となる細胞内認識機構や下流の遺伝子発現プログラムの活性化に至るシグナル伝達経路を明らかにすることを目的に研究を進めた結果、本年度においては、新しいシグナル制御因子ZAPSを同定するに至った。ZAPSは、PARP(poly(ADP-ribose)polymerase)スーパーファミリーに属するPARP-13のアイソフォームの1つであり、I型インターフェロン(IFN)によって誘導する遺伝子である。実際に、ZAPSを過剰発現させたヒトHEK293T細胞においてB型DNA(poly(dA-dT)・poly(dT-dA))をトランスフェクトすることで誘導されるIFN-β、TNF-α、IL-6、CXCL10 mRNAの発現誘導が大きく増強された。一方、HEK293T細胞においてZAPSの発現をsiRNAによって抑制した場合、B型DNAによるIFN-βmRNAの発現誘導が有意に抑制された。この際のIFN発現誘導に必須のIRF-3転写因子の二量体形成が抑制されることも見出している。これらの結果は、HEK293T細胞においてB型DNAによって誘導される自然免疫シグナル経路においておそらく上流でZAPS分子が正に制御していることが示唆された。また、蛍光顕微鏡による解析で、ZAPSは細胞質に存在し、B型DNAによる刺激によって顆粒状に集合体を形成することも見出した。ZAPSはN末端にzincフィンガーモチーフを複数有しているが、この領域を欠損した変異型ZAPSを用いた解析で、この領域がB型DNAによる自然免疫応答に必要であることを示した。以上の結果から、ZAPSはHEK293T細胞においてB型DNAによって誘導されるI型IFN発現をはじめとする自然免疫応答を増強する新しい宿主側の制御因子であることが示された。
    日本学術振興会, 特定領域研究, 北海道大学, 21022001
  • がんに対するIFNを組み合わせた新しい抗体治療ストラテジーの開発
    科学研究費助成事業
    2008 - 2009
    高岡 晃教
    これまでのI型インターフェロン(IFN)シグナルの研究をがん治療の領域において発展させた形で,がんの抗体治療の新しいストラテジーを提案し,臨床応用へ向けた分子基盤を見出すことを目的として研究を推進した.まず細胞表面のタンパク質をビオチン化させる方法を用いて,IFN-βに応答してがん細胞に比較的選択的にその発現レベルが顕著に増強する分子群を同定し,その結果,5つのターゲット分子に着目した.今年度,まず,これら5つの候補分子の細胞外領域に対するモノクローナル抗体の作製を行った.スクリーニングの結果,今年度内に抗体を用いた解析が可能となった2つのターゲットSCI101とSCI102について検討を進めた.皮下に担がんさせたマウスの系において,これらの抗体を用いて,IFN投与後の腫瘍内組織のターゲット分子のタンパク質発現レベルを経時的に検討したところ,昨年度検討した担がんSCIDマウスを用いた系での実験結果とconsistentな結果が得られた.
    SCI101の方がIFN刺激後16時間目をピークに24時間目にはその二分の一以下にタンパク質の発現レベルが低下するのに対し,SCI102はもう少し早い発現経過を示し,6時間目がピークで,24時間目にはほとんど発現レベルは無刺激のレベルに近くなる結果となった.次に,発現プロファイルを元に,IFN-β投与群と非投与群で治療抗体の抗腫瘍効果を検討した.発現ピークの1時間前に尾静脈より抗体投与を5日間行なった結果,IFN-β投与のみでも非投与群と比べ,腫瘍径の減少がみとめられたが,抗体投与を併用した群の方が,IFN-β投与のみよりもより,腫瘍が縮小する傾向がみとめられた.現在,数を増やして再現性を検討している.また蛍光物質をラベルした治療抗体を用いて,IFN投与による治療抗体の腫瘍局所への集積の検討を行っており,できるだけ早急に論文にまとめることを予定している.
    日本学術振興会, 特定領域研究, 北海道大学, 20015002
  • 脳神経系におけるIFNシステムの解析と新規固定型IFNの応用
    科学研究費助成事業
    2007 - 2009
    高岡 晃教
    本研究では,現在広く臨床応用されているIFN-α/β製剤に関して問題となっている副作用の軽減を目指し,より効率の良い効果をもたらすIFN分子の改良を試み,とくに脳神経系の腫瘍であるグリオーマに対する検討を行うこと,さらにはこれを発展させて,脳神経系の領域におけるIFN biologyの解明にもせまることを目的として昨年度より実験を進めてきた.本研究においては,ヒトIL-2受容体α鎖の細胞内領域および膜貫通領域をヒトIFN-βに融合させたタンパク質をデザインすることで,IFN-βを細胞膜表面に固定し,周囲への分散を抑制することによってIFNの副作用を抑えることを目指した.しかしながら,この膜結合型IFNは,膜表面に発現されるよりも細胞外に分泌されてしまう割合が9割をしめるという問題が浮上し,本年度は,この問題点を解決すべく,効率よく細胞膜に局在する分子を設計しなおすことを進めていた.まず,ヒトIL-2受容体α鎖とヒトIFN-βとの間に(Gly-Gly-Gly-Gly-Ser)x3という配列のリンカーを挟んで両者を結合させたタンパク質をデザインしていたが,そのリンカー部分の長さを変えることで検討したところ,当初の15個のアミノ酸残基数よりも長い50個のアミノ酸残基数に変えたところ,膜表面に発現される割合は5割までに改善されることを見出した.しかしながらまだ5割は細胞外に分泌されてしまうため,更なる改善が必要と考えられた.本年度,開始から1か月半を経た現時点で,若手(S)の研究費が支給されることに決まった.そのため,本研究費はその重複規定の剃限に従い,この時点をもって本課題に対する研究費の支給が停止されることになる.若手研究費による新たに始まる研究は感染やがんに対する自然免疫応答をとくにIFN応答を誘導するパターン認識受容体を介するシグナル伝達を解明するものであり,これまで行ってきた基盤(B)による研究結果も生かし,さらに発展させた研究を展開させていきたいと考えている.
    日本学術振興会, 基盤研究(B), 北海道大学, 19390109
  • Informatory expression system connecting cancer and immunity.
    Grants-in-Aid for Scientific Research
    2005 - 2009
    TANIGUCHI Tadatsugu; TAKAOKA Akinori; TAMURA Tonohiko; HONDA Kenya; OOBA Yuusuke; YANAI Hideyuki
    We investigated biological mechanisms and role of effecter molecules, e.g. interferons, IRFs and Noxa. It revealed that these molecules are involved in transformation, apoptosis induction and metastasis signaling pathways. We also found the cross-talk pathway between TLRs signaling. Moreover, we identified DAI and HMGB1, 2, 3 are important for the nucleic-acid mediated innate immune responses. Since these pathways regulate tumorgenesis and exacerbation, our findings will be proved to be useful for the development of novel tumor therapy in near future.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research on Priority Areas, The University of Tokyo, 17012005
  • IRFファミリー転写因子を介した感染防御の分子機構
    科学研究費助成事業
    2007 - 2008
    高岡 晃教
    これまで多くのIRFファミリーメンバーが病原体認識受容体下流で活性化を受け, 宿主細胞における自然免疫応答に関与することを示してきた. 昨年度, IRF-3やIRF-7の活性化を誘導する細胞質型DNA認識受容体の候補分子としてDAI(DML-1/ZBP1)を同定するに至ったが, 本年度は, このDAIに関する研究をさらに進め, DAIのリガンド特性や活性化機構の解析を行った. その結果, リコンビナントのDAI (DML-1/ZBP1) タンパク質を作製し, in vitroの系においてB型DNAとの直接的な結合を示すことができ, かつこの結合はB型DNAをはじめ, ISD (IFN-stimulatory DNA) や, Z-DNAをとることが知られているpoly(dG-dC)の過剰投与によって競合されることが示された. またDAI(DML-1/ZBP1)の活性化には, リガンドとして少なくとも100bp以上の長いDNAが必要であることおよび, DAI(DML-1/ZBP1)のN末側の2つのZα, Zβドメインに加え, D3ドメインの3つの領域が必要であることも見出した. さらに人工的にDAI(DML-1/ZBP1)分子の二量体を形成することでI型IFNsの発現の誘導がみとめられた.一方で, このようなDAI(DML-1/ZBP1)の細胞質DNA応答における役割はredundantなものであることを示す結果も得られた. 加えて, DAIと共通の保存された領域をもつ宿主由来のタンパク質ADAR1やウイルス由来のE3Lについて検討した結果, 共に細胞内DNA応答について負に制御していることが明らかとなった.
    日本学術振興会, 特定領域研究, 北海道大学, 19041021
  • Functional analyses on roles of intetferon-IRF-family transcriptional factor
    Grants-in-Aid for Scientific Research
    2004 - 2005
    TAKAOKA Akinori; HONDA Kenya
    In this study, we analyzed the molecular mechanism for antiviral defense triggered by interferon-α / (IFN-α/β) and the signalling pathways which lead to type I IFN gene induction by TLR activation. In particular, we focused on IFN-regulatory factors (IRFs), which are known to be essential factors upon viral infection, and have elucidated several novel roles of the IFN-IRF system in activation of innate immune response. First, we found that the level of p53 gene, which is known to encode a tumor suppressor, is upregulated by IFN treatment through activation of ISGF3 transcriptional complex, contributing to enhancement of p53 response to stress signals. We showed that p53 is phosphorylated and activated upon viral infection, and that p53 is essentially involved in the induction of apoptosis in virally infected cells. This result demonstrated an interrelationship between IFN-α/β signaling and p53-mediated response, which provided a novel aspect in terms of a linkage between tumor suppression and immunity. Second, we analyzed various hideficient mice to show that IRF-7 mediates a novel MyD88-dependent pathway for the induction of type I IFN gene expression by TLR9 subfamily members in plasmacytoid dendritic cells (pDCs). In addition, we found a spaciotemporal regulation, by which pDCs are capable to produce high levels of IFN- α/β. On the other hand, IRF-5 is found to be essentially involved in TLR-mediated production of proinflammatory cytokines. Recently, we also found that IRF-5 is activated upon viral infection and plays a role in virus-induced apoptosis in a distinct manner from p53. Another IRF-family member, IRF-4, is shown to be a negative regulator of IRF-5 by competitively inhibiting the interaction of IRF-5 with MyD88. Thus, we demonstrated that IRF-family transcriptional factors are critical downstream mediators of TLRs to regulate the activation of innate immune response.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research on Priority Areas, University of Tokyo, 16017220
  • Gene expression network for tumor suppression
    Grants-in-Aid for Scientific Research
    2000 - 2004
    TANIGUCHI Tadatsugu; TAKAOKA Akinori; HONDA Kenya
    In the current study, we have made multifaceted approach to elucidate molecular mechanisms for oncogenesis, by analyzing not only the interrelationships between molecules which are involved in tumor suppression but also the gene expression network from both genetic and epigenetic aspects. Specifically, we found several important roles of "weak signal" by constitutively produced IFN-α/β in IFN-γ or IL-6-mediated cellular response as well as regulatory systems for cancer prevention. We also found a novel cross-talk mechanism between RANKL and IFN-γ, and clarified the regulatory role of the IFN system in osteoclast differentiation, which provided its putative therapeutic application to bone destruction by metastatic tumors. Development of autoimmune-like disease was observed in mice lacking IRF-2, which is an attenuator of IFN-a/β signaling. Further analyses revealed the role of IFN-α/β signaling in the regulation of CD8^+ T cell response. In these IRF-2-deficient mice, such hyperactivation of IFN-α/β signaling affects normal differentiation of dendritic cells. IFN-α/β signaling is also found to be indispensable during DC maturation. Furthermore, it was demonstrated that another IRF-family member, IRF-7, is an essential transcriptional factor for the IFN induction in plasmacytoid DCs in response to unmethylated DNA (CpG), which is known to be a potent adjuvant for anti-tumor immunity. And we found a spaciotemporal regulation, by which plasmacytoid DCs are capable to produce IFN-α/β at high levels. On the other hand, IRF-5 is also found to be essentially involved in the CpG-induced production of proinflammatory cytokines. In addition, we identified novel p53 target genes, Noxa and Reprimo, which are involved in p53-mediated apoptosis or cell cycle arrest, respectively. Further study by generating Noxa-deficient mice revealed that Noxa may be a beneficial therapeutic target since it undergoes selective apoptosis in oncogene-expressing cells. Finally, we found an interrelationship between IFN-α/β signaling and p53-mediated response, which provided a novel aspect in terms of a linkage between tumor suppression and immunity.
    Taken together, we believe that these research accomplishments contribute to some advance in understanding molecular mechanisms underlying tumor suppression, and provide a molecular basis for their clinical applications.
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research on Priority Areas, The University of Tokyo, 12219204
  • 感染防御系におけるIFN及びIFN調節因子活性化の役割とその分子基盤の解析
    科学研究費助成事業
    2003 - 2003
    高岡 晃教; 本田 賢也
    本年度,抗ウイルス免疫応答系においてIFNとp53との新しい関連性を報告した.癌抑制因子であるp53の遺伝子がIFN-α/βによって発現誘導されることを見出した.また,p53はウイルス感染によってリン酸化され,活性化されることも明らかにした.p53欠損細胞では水庖性口内炎ウイルス(VSV)感染によるアポトーシスが阻害され,結果的には上清中のウイルス産生のレベルが野生型細胞の場合と比較して著明に高くなる結果を得た.更にP53欠損マウスが野生型マウスに比べ,VSVに対して感受性であり,また,ウイルスが過剰に増殖し,死亡に至る割合が高いことが見出された.さらに,IFNAR1欠損細胞を用いた解析より,ウイルス感染により産生されるIFN-α/βによって誘導されたp53も同様の役割を担っていることが示された.即ち,ウイルスによって活性化されたp53は感染細胞を迅速かつ効率のよい細胞死をもたらすことによってウイルスの複製や周囲への拡散を抑制することに寄与していると考えられた.一方,IFN-α/βはウイルスのみならず様々な病原体関連分子により樹状細胞において発現が誘導され,樹状細胞の成熟・活性化に重要な役割を担っていることも明らかにした.即ち,マクロファージや樹状細胞においてLPSや二本鎖RNA刺激によりIFN-α/β遺伝子の発現誘導が認められ,その誘導にIRF-3やIRF-7が関与しているという結果を得た.また,ウイルス感染時における樹状細胞の活性化はIFN-α/β依存性であることも見出した.二本鎖RNAの認識受容体であるTLR3とPKRの発現誘導がIFN-α/βにより転写レベルで制御されていることも明らかにした.更に,IFN-α/βはTLR3,PKRのみならず,それ以外にもウイルス認識に関わる分子群の誘導に関わっているという結果をTLR3,PKR欠損マウスを用いた検討から明らかにした.
    日本学術振興会, 特定領域研究, 東京大学, 15019021
  • 感染免疫システムにおける多様なシグナル伝達経路の活性化とその意義に関する研究
    科学研究費助成事業
    2002 - 2002
    高岡 晃教; 本田 賢也
    インターフェロン(IFN)-α/βによるToll-like receptors (TLRs)シグナルの増幅を介した,樹状細胞活性化に関わる新たな機構を明らかにした、TLRsは,病原体由来のPAMPs (pathogen-associated molecular patterns)を認識する生体側の受容体として知られているが,TLRを介するシグナルは,樹状細胞の二次リンパ組織のT細胞領域への移入並びに,成熟を促すことが知られている.中でもTLR3は,ウイルス関連分子の二本鎖RNAを認識することにより,効率的な抗ウイルス応答を誘導する重要な役割を担っていると考えられている.我々は,このTLR3が,自然免疫系において中心的な役割を持つIFN-α/βにより,mRNAレベルで誘導されることで,TLR3を介するシグナル伝達系が増幅されることを見出した.実際に,樹状細胞において,二本鎖RNAによる二相性の活性化メカニズムが存在することが示された.すなわち,初期では,二本鎖RNAによってIFN遺伝子が誘導される.後期では,初期で誘導されたIFN-α/βを介したシグナルによって,TLR3の発現が引き起こされることにより,TLR3シグナルの増幅へとつながることが明らかになった.IFN-α/βシグナルの入らないIFN受容体欠損(IFNAR1^<-/->)マウスでは,二本鎖RNAに対する樹状細胞の成熟障害が認められるが,興味深いことに,このIFNAR1^<-/->マウス由来の樹状細胞にTLR3のみを発現させることにより,その成熟障害が回復した.さらに我々は,IFNAR1^<-/->マウスにおいては,樹状細胞における二本鎖RNAあるいはRNAウイルスに対する成熟応答が認められないものの,T細胞領域への移入は正常に起こることも見出した.つまり,樹状細胞の二次リンパ組織への移動と成熟は異なるメカニズムによって制御されていることも明らかにした.
    以上の結果より,本研究では,IFN-α/βによるTLR3シグナルの増幅系により,樹状細胞での二本鎖RNAによる二相性の活性化メカニズムが存在することを明らかにした.このようにIFN-α/βを介するTLR3シグナルの増幅は,ウイルスに対する免疫応答をより高めるために生体が獲得した制御機構であると考えられ,さらにこのことは,自然免疫系と適応免疫系との新たな連携機構の存在を示唆している.
    日本学術振興会, 特定領域研究, 東京大学, 14021017
  • Studies about novel roles of the membrane domain in signal transduction systems
    Grants-in-Aid for Scientific Research
    2001 - 2002
    TAKAOKA Akinori; TANAKA Nobuyuki
    Cross talk between distinct receptor components is often important to amplify, suppress or modulate a given receptor signalling pathway by the other, and this is an aspect critical to generate diversity of cellular responses. In this study, we sought to explore a novel regulatory mechanism(s) in cytokine signal transduction, particularly in terms of the possible involvement of membrane domains in signalling efficiency, specificity and cross talk among cytokine signallings. In this context, we previously reported on the critical role of the IFN-α/β signalling complex, generated by constitutively produced IFN-α/(3, in IFN-γ signalling. As a result of the extended study, here, we found a novel cross talk between interferon (IFN)-α/β and interleukin (IL)-6 signallings, wherein the constitutive, weak IFN-α/β signalling also contributes to enhance the IL-6 signalling. The previous and present studies showed that the receptor components for IFN-α/β, IFN-γ, and IL-6 were concentrated in caveolar membrane fractions, i.e., membrane domains. This suggests that these receptor components seem to be in close proximity to forma mulli-subunit complex, which may be termed "receptosome", so as to make efficient signalling for these cytokines. In addition, these results show a possibility that these membrane domains play a role as a signalling scaffold for these receptor components during the cytokine signalling.
    Through these series of studies, we demonstrated a unique facet of a weak signalling by IFN-α/β, which is constitutively produced at a low level in the absence of viral infection. In fact, we additionally found that this weak signal also contributes to amplification of IFN-α/β production in response to viral infection. Therefore, this weak signalling, described in the context of what we propose as a "revving-up system", was found to provide a foundation for a more efficient and robust signalling in host defense.
    We also showed the possible role of the constitutive, weak IFN-α/β signalling in suppression of oncogenesis, in terms of a unique tumor urveillance system. Furthermore, we found a novel inter-relationship between IFN-α/β signalling and p53 response in tumor suppression, which may provide a possible underlying mechanism to the direct effect of IFN in tumor suppression.
    Taken together, we believe that these research accomplishments made progress in the study on the elucidation of advanced complex mechanisms for the regulation of cellular signalling events, and that further extended studies will provide any contributions not only to the elucidation of underlying signalling aspects which cause cancer or autoimmune diseases, but to their therapeutic applications
    Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), The University of Tokyo, 13680772
  • 感染免疫システムにおける多様なシグナル伝達経路の活性化とその意義に関する研究
    科学研究費助成事業
    2001 - 2001
    芫岡 晃教; 本田 賢也
    IRF (interferon regulatory factor)-7遺伝子欠損マウスを作製し,このマウス由来の胎仔線維芽細胞(MEF)を用いて,ウイルス感染時におけるinterferon (IFN)産生について検討を行った.Northern blottingの結果,IFN-αのmRNAの誘導が全く認められず,IFN-βのmRNAの発現も著明に減弱していた.同様の結果が,IRF-7遺伝子欠損マウスの脾細胞についても得られた.以上の結果より,IRF-7を介したpositive feedbackメカニズムの重要性が確証された.
    次に,樹状細胞の活性化におけるIFN-IRF系の役割について分子レベルで検討した.樹状細胞は,骨髄細胞をGM-CSF存在下で6日間培養した後,MACSでCD11c陽性細胞のみをsortして得られたものを用いた.その結果,IFN-βが,pathogen-associated molecules (PAMs)である,lipopolysaccharide (LPS)やdouble strand RNA (dsRNA),非メチル化DNAのCpGによっても,誘導されることが示された.しかしながら,IFN-αの誘導はpolyI : C刺激時においてのみ認めた.IRF-3遺伝子欠損マウス由来の樹状細胞においては,LPSやpolyI : C刺激後においてIFN-βの発現が著明に低下していたが,CpG刺激後においてはわずかに低下を認めるのみであった.一方IRF-7遺伝子欠損マウス由来の樹状細胞においては,polyI : C刺激後のIFN-βの発現誘導は減弱したが,LPS刺激後においてはあまり変化を認めなかった.さらに,IFNAR1遺伝子欠損マウス由来の樹状細胞においては,polyI : C刺激後,MHC class IIのupregulationは正常に起こるが,MHC class Iやcostimulatory moleculesのupregulationがおこらず,またallo stimulatory activityも特にCD8T細胞に対して著しく低下していた.しかしながら,PAMs刺激後共通に起こることではなく,LPSやCpG刺激後allo stimulatory activityにおいて,IFNAR1遺伝子欠損マウスと野生型マウス間においてpolyI : C刺激時のような著明な差は認められなかった.以上の結果より,PAMs刺激において,樹状細胞はToll-like receptorを介して様々なeffector分子とともに,IFNを誘導し,その誘導には,IRF-3/7が関与していることが示されたが,ウイルス感染とは異なったシグナルカスケードが関与していることが示唆された.また,特にdsRNA刺激を受けた樹状細胞において,IFN-α/βによってCD8+T細胞の応答をより増強する方向に働くことも示唆された.
    日本学術振興会, 特定領域研究(C), 東京大学, 13226013
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    24 Feb. 2015
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