Regeneration of immune severance system by the repertoire regulation

• Project/Area Number: 15078102
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: RIKEN (2004-2006); Tokyo University of Science (2003)
• Principal Investigator: KUBO Masato Kubo Laboratory for Signal Network, Research Center for Allergy and Immunology (RCAI), RIKEN Yokohama Institute, シグナル・ネットワーク研究チーム, チームリーダー (40277281)
• Co-Investigator(Kenkyū-buntansha): 樗木 俊聡 秋田大学, 医学部寄生虫学, 教授 (50233200)
• Project Period (FY): 2003 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥122,000,000 (Direct Cost: ¥122,000,000); Fiscal Year 2006: ¥27,800,000 (Direct Cost: ¥27,800,000); Fiscal Year 2005: ¥27,800,000 (Direct Cost: ¥27,800,000); Fiscal Year 2004: ¥26,400,000 (Direct Cost: ¥26,400,000); Fiscal Year 2003: ¥40,000,000 (Direct Cost: ¥40,000,000)
• Keywords: Cytokine / Suppression / Signal / septic peritonitis / liver injury / T cell / メモリーT細胞 / T細胞機能分化 / サイトカインバランス / Th1 / Th2 / 免疫監視 / IL-4 / SOCS

Research Abstract

Cytokine regulate the survival, proliferation, differentiation and function of immune cells as well as cells from most other organ systems. Many of these cytokines induce the expression of SOCS proteins, a feedback inhibitor of JAK kinase. It still remains unclear how cytokine signaling regulates immune homeostasis. In this year, we studied a role of SOCS5 in septic peritonitis, and demonstrate that overexpression of SOCS5 in T cells augments innate immunity during septic peritonitis induced by cecal ligation and puncture (CLP). We also studied the role of SOCS proteins in acetaminophen (APAP)-induced acute liver injury. We demonstrate that forced expression of SOCS3 in T cells exacerbates APAP-hepatotoxicity, indicating that novel sight of SOCS3 function in innate immunity. In order to study naive and memory T cell development in the attenuated cytokine signaling, we generated the T cell specific SOCS1 transgenic lines (SOCS1Tg), and we demonstrated that the cytokine signalings was essential for survival of naive CD4 T cells in the periphery. These data demonstrated that SOCS proteins are key physiological regulators of both innate and adaptive immunity. These molecules positively and negatively regulate macrophage and dendritic-cell activation and are essential for T-cell development and differentiation. We recently reviewed these studies on SOCS proteins and their role in immunity (Nature Review Immunology).

Research Products

• [Journal Article] The role of IL-7/STAT5 pathway and suppressor of cytokine signaling 1 in maintenance of naive and memory CD4 T cells in peripheral lymphoid organs. (2007)
  • Author(s): Seki, Y, Yang, J, Okamoto, M, Tanaka, S, Goizuka, R, Farrar, M, A, Kubo, M.
  • Journal Title: The Journal of Immunology 1,178(1) Pages: 262-270
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Role of endogenous inhibitors of cytokine signaling in allergic asthma. (2007)
  • Author(s): Inoue, H, Fukuyama, S, Kubo, M, Yoshimura, A.
  • Journal Title: Current Medicinal Chemistry 14 Pages: 181-189
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Overexpression of Suppressor of Cytokine Signaling-3 in T cells Exacerbates Acetaminopheninduced Hepatotoxicity. (2007)
  • Author(s): Numata K, Kubo, M, Watanabe, H, Takagi, K, Mizuta, H, Okada, S, Ito, T, Matsukawa, A
  • Journal Title: The Journal of Immunology 178 Pages: 3777-3785
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Involvement of the Programmed Death-1/Programmed Death-1 Ligand Pathway in CD4-CD25-Regulatory T-Cell Activity to Suppress Alloimmune Responses (2007)
  • Author(s): Kitazawa, Y, Fujino, M, Wang, Q, Kimura, H, Azuma, M, Kubo, M, Abe, R, Li, X-K.
  • Journal Title: Transplantation 83 Pages: 774-782
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] SOCS proteins, cytokine signalling and immune regulation. (2007)
  • Author(s): Yoshimura, A, Naka, T, Kubo, M.
  • Journal Title: Nature Review Immunology (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The role of IL-7/STAT5 pathway and suppressor of cytokine signaling 1 in maintenance of naive and memory CD4 T cells in peripheral lymphoid organs. (2007)
  • Author(s): Seki, Y., Yang, J., Okamoto, M., Tanaka, S., Goizuka, Farrar, M.A., R., Kubo, M.
  • Journal Title: J. Immunol. 1;178(1) Pages: 262-70
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Role of endogenous inhibitors of cytokine signaling in allergic asthma, (2007)
  • Author(s): Inoue, H., Fukuyama, S., Kubo, M., Yoshimura, A.
  • Journal Title: Cur. Med. Chem. 14 Pages: 181-189
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Overexpression of Suppressor of Cytokine Signaling-3 in T cells Exacerbates Acetaminophen-induced Hepatotoxicity. (2007)
  • Author(s): Numata, K., Kubo, M., Watanabe, H., Takagi, K., Mizuta, H., Okada, S., Ito, T., Matsukawa, A.
  • Journal Title: J. Immunol. 178 Pages: 3777-3785
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement of the Programmed Death-1/Programmed Death-1 Ligand Pathway in CD4-CD25- Regulatory T-Cell Activity to Suppress Alloimmune Responses (2007)
  • Author(s): Kitazawa, Y., Fujino, M., Wang, Q., Kimura, H., Azuma, M., Kubo, M., Abe, R., Li, X-K.
  • Journal Title: Transplantation 83 Pages: 774-782
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] SOCS proteins, cytokine signalling and immune regulation. (2007)
  • Author(s): Yoshimura, A., Naka, T., Kubo, M.
  • Journal Title: Nature Review Immunology
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The role of IL-7/STAT5 pathway and suppressor of cytokine signaling 1 in maintenance of naive and memory CD4 T cells in peripheral lymphoid organs. (2007)
  • Author(s): Seki, Y., Yang, J., Okamoto, M., Tanaka, S., Goizuka, Farrar, M.A., R., Kubo, M.
  • Journal Title: The Journal of Immunology 1;178(1) Pages: 262-270
• [Journal Article] Role of endogenous inhibitors of cytokine signaling in allergic asthma (2007)
  • Author(s): Inoue, H., Fukuyama, S., Kubo, M., Yoshimura, A.
  • Journal Title: Current Medicinal Chemistry 14 Pages: 181-189
• [Journal Article] Overexpression of Suppressor of Cytokine Signaling-3 in T cells Exacerbates Acetaminophen-induced epatotoxicity. (2007)
  • Author(s): Numata, K., Kubo, M., Watanabe, H., Takagi, K., Mizuta, H., Okada, S., Ito, T., Matsukawa, A.
  • Journal Title: The Journal of Immunology (in press)
• [Journal Article] SOCS proteins, cytokine signalling and immune regulation. (2007)
  • Author(s): Yoshimura, A., Naka, T., Kubo, M.
  • Journal Title: Nature Review Immunology (in press)
• [Journal Article] Computer Simulation of the Role of SOCS Family Protein in THelper Cell Differentiation. (2006)
  • Author(s): Yamada, S, Tsukada, J, Yoshimura, A, Kubo, M.
  • Journal Title: international lmmunology 18 Pages: 335-345
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Activation of the arylhydrocarbon receptor in the thymocytes induces thymocyte reduction independently of Fas/Fas ligand signaling pathway. (2006)
  • Author(s): Nagai, H, Kubo, M, Abe, R, Yamamoto, M, Nohara, K.
  • Journal Title: International Immunopharmacology 6 Pages: 276-286
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Suppressor of Cytokine Signaling 3 (SOCS3) in the Th2 cells evokes Th2 cytokines, lgE and eosinophilia. (2006)
  • Author(s): Kubo, M, Inoue, H.
  • Journal Title: Current Allergy and Asthma Reports 9 Pages: 32-39
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Suppressor of cytokine signaling-1 in lymphocytes regulates development of experimental colitis and inflammatory bowel disease (2006)
  • Author(s): Inagaki-Ohara K, Sasaki, A, Matsuzaki, G, Ikeda, T, Sakamoto, Y, Hotokezaka, M, Chijiiwa, K, Nawa, Y, Kubo, M, Yoshida, H, Yoshimura A.
  • Journal Title: Gut 55 Pages: 212-219
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Contribution of interleukin-18 to atopic dernatutus-like skin inflammation induced by staphylococcus aureus product in mice (2006)
  • Author(s): Terada, M, Tsutsui, H, Imai, Y, Yasuda, K, Mizutani, H, Yamanishi, K, Kubo, M, Matsui, K, Sano, H, Nakanishi, K.
  • Journal Title: Proc. Natl. Acad. Sci. USA 103 Pages: 8816-8821
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The interleukin-4 (IL-4) ebgabcer CNS-2 is regulated by Notch/RBP-J signals and controls initial IL-4 expression in NKT cells and memory-type CD4 T cells. (2006)
  • Author(s): Tanaka, S, Tsukada, J, Suzuki, W, Hayashi, K, Tanigaki, K, Tsuji, M, Honjo, T, Kubo, M.
  • Journal Title: Immunity 24 Pages: 689-701
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Role of suppressor of cytokine signaling in ocularallergy. (2006)
  • Author(s): Kubo, M, Ozaki, A, Tanaka, S, Okamoto, M, Fukushima, A.
  • Journal Title: Current Opinion in Allergy ＆ Clinical Immunology 6 Pages: 361-366
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Overexpression of Suppressor of cytokine signaling-5 in T cells augments innate immunity during septic peritonitis. (2006)
  • Author(s): Watanabe, H, Kubo, M, Numata, K, Takagi, K, Mizuta, H, Okada, S, Ito, T, Matsukawa, A.
  • Journal Title: The Journal of Immunology 15,177(12) Pages: 8650-8657
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Computer Simulation of the Role of SOCS Family Protein in T Helper Cell Differentiation. (2006)
  • Author(s): Yamada, S., Tsukada, J., Yoshimura, A, Kubo, M.
  • Journal Title: Int. Immunol. 18 Pages: 335-345
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Activation of the aryl hydrocarbon receptor in the thymocytes induces thymocyte reduction independently of Fas/Fas ligand signaling pathway. (2006)
  • Author(s): Nagai, H., Kubo, M., Ryo Abe, R., Yamamoto, M., Nohara., K.
  • Journal Title: International Immunop.harmacology 6 Pages: 276-286
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Suppressor of Cytokine Signaling 3 (SOCS3) in the Th2 cells evokes Th2 cytokines, IgE and eosinophilia (2006)
  • Author(s): Kubo, M., Inoue, H.
  • Journal Title: Current Allergy and Asthma Reports 9 Pages: 32-39
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Suppressor of cytokine signaling-1 in lymphocytes regulates development of experimental colitis and inflammatory bowel disease (2006)
  • Author(s): Inagaki-Ohara, K., Sasaki, A., Matsuzaki, G., Ikeda, T., Sakamoto, Y., Hotokezaka, M., Chijiiwa, K., Nawa, Y., Kubo, M., Yoshida, H., Yoshimura A.
  • Journal Title: Gut 55 Pages: 212-219
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Contribution of interleukin-18 to atopic dermatitis-like skin inflammation induced by Staphylococcus aureus product in mice. (2006)
  • Author(s): Terada, M., Tsutsui, H., Imai, Y., Yasuda, K., Mizutani, H., Yamanishi, K., Kubo, M., Matsui, K., Sano, H., Nakanishi, K.
  • Journal Title: Proc. Natl. Acad. Sci. USA 103 Pages: 8816-8821
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The interleukin-4 (IL-4) enhancer CNS-2 is regulated by Notch/RBP-J signals and controls initial IL-4 expression in NKT cells and memory-type CD4 T cells. (2006)
  • Author(s): Tanaka, S., Tsukada, J., Suzuki, W., Hayashi, K., Tanigaki, K., Tsuji, M., Honjo, T., Kubo, M.
  • Journal Title: Immunity 24 Pages: 689-701
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Role of suppressor of cytokine signaling in ocular allergy. (2006)
  • Author(s): Kubo, M, Ozaki, A., Tanaka, S., Okamoto, M., Fukushima, A.
  • Journal Title: Cur. Opin. Alter. Clin. Immunol. 6 Pages: 361-366
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Overexpression of Suppressor of cytokine signaling-5 in T cells augments innate immunity during septic peritonitis. (2006)
  • Author(s): Watanabe, H., Kubo, M., Numata, K., Takagi, K., Mizuta, H., Okada, S., Ito, T., Matsukawa, A.
  • Journal Title: J. Immunol. 15;177(12) Pages: 8650-8657
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Computer Simulation of the Role of SOCS Family Protein in T Helper Cell Differentiation. (2006)
  • Author(s): Yamada, S., Tsukada J., Yoshimura, A, Kubo, M.
  • Journal Title: International Immunology 18 Pages: 335-345
• [Journal Article] Activation of the aryl hydrocarbon receptor in the thymocytes induces thymocyte reduction independently of Fas/Fas ligand signaling pathway. (2006)
  • Author(s): Nagai, H., Kubo, M., Ryo Abe R., Yamamoto, M., Nohara., K.
  • Journal Title: International Immunopharmacology 6 Pages: 276-286
• [Journal Article] Contribution of interleukin-18 to atopic dermatitis-like skin inflammation induced by Staphylococcus aureus product in mice (2006)
  • Author(s): Terada, M., Tsutsui, H., Imai, Y., Yasuda, K., Mizutani, H., Yamanishi, K., Kubo, M., Matsui, K., Sano, H., Nakanishi, K.
  • Journal Title: Proc. Natl. Acad. Sci. USA 103 Pages: 8816-8821
• [Journal Article] Role of suppressor of cytokine signaling in ocular allergy. (2006)
  • Author(s): Kubo, M, Ozaki, A., Tanaka, S., Okamoto, M., Fukushima, A.
  • Journal Title: Current Opinion in Allergy ＆ Clinical Immunology 6 Pages: 361-366
• [Journal Article] Overexpression of Suppressor of cytokine signaling-5 in T cells augments innate immunity during septic peritonitis. (2006)
  • Author(s): Watanabe, H., Kubo, M., Numata, K., Takagi, K., Mizuta, H., Okada, S., Ito, T., Matsukawa, A.
  • Journal Title: The Journal of Immunology 15;177(12) Pages: 8650-8657
• [Journal Article] Stat5a Inhibits IL-12-induced Th1 cell Differentiation through the Induction of SOCS3 Expression. (2005)
  • Author(s): Takatori, H., et al.
  • Journal Title: J.Immunol. 174 Pages: 4105-4112
• [Journal Article] Induction of T-helper (Th1) cell type immune response by dendritic cells lacking the suppressors of cytokine signaling-1 (SOCS1) gene. (2005)
  • Author(s): Hanada, T., et al.
  • Journal Title: J.Immunol. 174 Pages: 4325-4332
• [Journal Article] Mite-antigen stimulation of MAL expression in peripheral blood T cell of atopic patients. (2005)
  • Author(s): Yoshida, N-L., et al.
  • Journal Title: Allergology International 54 Pages: 273-282
• [Journal Article] Induction and Activation of the Aryl Hydrocarbon Receptor by Interlukin-4 in B cells. (2005)
  • Author(s): Tanaka, G., et al.
  • Journal Title: Int.Immunol. 17 Pages: 797-805
• [Journal Article] The role of suppressor of cytokine signaling 1 as a negative regulator for aberrant expansion of CD8α^+ dendritic cell subset. (2005)
  • Author(s): Tsukada, J., et al.
  • Journal Title: Int.Immunol. 17 Pages: 1167-1178
• [Journal Article] The control of allergic conjunctivitis by suppressor of cytokine signaling (SOCS) 3 and SOCS5. (2005)
  • Author(s): Ozaki, A., et al.
  • Journal Title: J.Immunol. 175 Pages: 5489-5497
• [Journal Article] Computer Simulation of the Role of SOCS Family Protein in T Helper Cell Differentiation. (2005)
  • Author(s): Yamada, S., et al.
  • Journal Title: Int.Immunol. 18 Pages: 335-345
• [Journal Article] Activation of the aryl hydrocarbon receptor in the thymocytes induces thymocyte reduction independently of Fas/Fas ligand signaling pathway. (2005)
  • Author(s): Nagai, H., et al.
  • Journal Title: International Immunopharmacology 6 Pages: 276-286
• [Journal Article] Suppressor of Cytokine Signaling 3 (SOCS3) in the Th2 cells evokes Th2 cytokines, IgE and eosinophilia (2005)
  • Author(s): Kubo, M., et al.
  • Journal Title: Current Allergy and Asthma Reports(review) 9 Pages: 32-39
• [Journal Article] 特集「免疫難病へのストラテジー;最新トピックス」SOCS3と自己免疫病およびアレルギー (2005)
  • Author(s): 久保 允人
  • Journal Title: 分子リウマチ 2 Pages: 15-21
• [Journal Article] Th1/Th2細胞の発見、そして制御機構の解明へ (2005)
  • Author(s): 久保 允人
  • Journal Title: Th1/Th2細胞の発見、そして制御機構の解明へ 8 Pages: 117-127
• [Journal Article] 自然免疫と獲得免疫の基礎:Th1/Th2バランスと感染防御 (2005)
  • Author(s): 久保 允人
  • Journal Title: 最新医学 60 Pages: 614-625
• [Journal Article] Th1/Th2細胞の機能分化 (2005)
  • Author(s): 久保 允人
  • Journal Title: 「臨床免疫学(上)-基礎研究のシンポと最新の臨床」山本一彦編集 日本臨床 2005年増刊 Pages: 355-363
• [Journal Article] SOCSとTh1/Th2分化とアレルギー炎症の制御 (2005)
  • Author(s): 久保 允人
  • Journal Title: 炎症・再生 25 Pages: 436-441
• [Journal Article] ナイーブCD4+T細胞の生存維持におけるサイトカイン (2005)
  • Author(s): 関 陽一
  • Journal Title: 臨床免疫 44 Pages: 482-488
• [Journal Article] IL-4-induced GATA-3 expression is a time-restricted instruction switch for type 2 helper T cell differentiations. (2004)
  • Author(s): Seki, N., Suzuki, W., Hayashi, K., Miyazaki, M., Izuhara, K., Brombacher, F., Kubo, M.
  • Journal Title: J.Immunol. 172 Pages: 6158-6166
• [Journal Article] Regulation of αβ/γδ T cell lineage commitment and peripheral T cell response by Notch/RBP-J signaling. (2004)
  • Author(s): Tanigaki, K., Tsuji, M., Han, H., Yamamoto, N., Tsukada, J., Inoue, H., Kubo, M., Honjo, T.
  • Journal Title: Immunity 20 Pages: 611-622
• [Journal Article] Suppressor of cytokine signaling-3 (SOCS3) regulates onset and maintenance of type 2 helper T cell mediated allergic responses. (2003)
  • Author(s): Seki, Y., Inoue, H., Nagata, N., Hayashi, K., Satoru Fukuyama, S., Matsumoto, K., Komine, O., Hamano, S., Himeno, K., Inagaki, K., Cacalano, N., O'Garra, A., Oshida, T., Saito, H., Johnston, J.A., 'Yoshimura, A., Kubo, M.
  • Journal Title: Nature Medicine 9,8 Pages: 1047-1054
• [Journal Article] Suppressor of cytokine signaling-1 (SOCS1) is essential for suppressing dendritic cell activation and systemic autoimmunity. (2003)
  • Author(s): Hanada, T., Inagaki-Ohara, K., Yoshida, H., Kato, S., Tsukada, J., Nomura, Y., Mimata, H., Kubo, M., Yoshimura, A.
  • Journal Title: Immunity 19,9 Pages: 437-450
• [Journal Article] Suppressor of cytokine signaling and immunity (2003)
  • Author(s): Kubo, M., Hanada, T., Yoshimura, A.
  • Journal Title: Nature Immunology 4,12 Pages: 1169-1176
• [Journal Article] The Runx1 transcription factor Inhibits the differentiation of naive CD4^+ T Cells into the Th2 lineage by repressing GATA3 expression. (2002)
  • Author(s): Komine, O., Hayashi, K., Natsume, W., Seki, Y., Seki, N., Yagi, R., Suzuki, W., Watanabe, T., Tamauchi, H., Hozumi, K., Habu, S., Satake, M., Kubo, M.
  • Journal Title: J.Exp.Med. 198,1 Pages: 51-61
• [Book] サイトカイン・ケモカインのすべて-基礎から最新情報まで- (2004)
  • Author(s): 笠倉新平, 松島綱治編集
  • Total Pages: 685
  • Publisher: 日本医学館
• [Publications] Yagi, R., Suzuki, W., Seki, N., Inoue, T., Kohyama, M., Arai, T., Kubo, M.: "The IL-4 Production Capability of Different Strains of Naive CD4^+ T cells controls the Direction of the Helper T cell response"International Immunology. 14. 1-11 (2002)
• [Publications] Yagi, R., Nagai, H., Iigo, Y., Akimoto, T., Arai, T., Kubo, M: "Development of the atopic dermatitis (AD)-like skin lesions in signal transducers and activators of transcription (STAT) 6 deficient NC/Nga mice."Journal of Immunology. 168. 2020-2027 (2002)
• [Publications] Arima, M., Toyama, H., Ichii, H., Kojima, S., Okada, S., Hatano, M., Cheng, G., Kubo, M., Fukuda, T., Tokuhisa, T.: "A putative silencer element in the IL-5 gene recognized by Bcl6."Journal of Immunology. 169. 829-836 (2002)
• [Publications] Seki, Y., Hayashi, K., Seki, N., Matsumoto, A., Seki, N., Tsukada, J., Ransom, J., Naka, T., Kishimoto, T., Yoshimura, A., Kubo, M.: "Selective expression of suppressor of cytokine signaling-5 (SOCS5) in type 1 helper T cell negatively regulates IL-4 dependent STAT6 activation."Proc.Natl.Acad.Sci.USA. 99. 13003-13008 (2002)
• [Publications] Kinjyo I, Hanada T, Inagaki-Ohara K, Mori H, Aki D, Ohishi M, Yoshida H, Kubo M, Yoshimura, A.: "SOCS-1/JAB is a negative regulator for LPS-induced macrophage activation."Immunity. 17,5. 583-591 (2002)
• [Publications] Matsumoto, A., Seki, Y., Watanabe, R., Hayashi, K., Johnston, J.A., Harada, Y., Abe, R., Yoshimura, A., Kubo, M: "A role of Suppressor of Cytokine Signaling-3 (SOCS3/CIS3/SSI3) is CD28 mediated IL-2 production."J.Exp.Med.. 197. 425-436 (2003)