Development of therapeutic strategy for allergic diseases based on the genome information

• Project/Area Number: 17390293
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Laboratory for Signal Network, Research Center for Allergy and Immunology (RCAI), RIKEN Yokohama Institute
• Principal Investigator: KUBO Masato RIKEN Yokohama Institute, Laboratory for Signal Network, Center for Allergy and Immunology (RCAI), 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): 八木 良二 独立行政法人理化学研究所, シグナル・ネットワーク研究チーム, 研究員 (20392152)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥15,300,000 (Direct Cost: ¥15,300,000); Fiscal Year 2006: ¥7,400,000 (Direct Cost: ¥7,400,000); Fiscal Year 2005: ¥7,900,000 (Direct Cost: ¥7,900,000)
• Keywords: IL-4 / Chromatin / Notch / Memory T cell / Transcriptional factor / IL-2

Research Abstract

From our previous study, the expression of IL-4 gene is found to be epigenetically regulated in CD4^+ T cells. However, these gene regulation mechanisms are virtually unclear. Therefore, we investigated the role of an evolutionarily conserved 〜200bp non-coding sequence in the intergenic region between IL-4 and KIF3 genes using GFP reporter transgenic (Tg) mice. Notch signals have been shown to affect the cellular differentiation of tissue throughout the life of multicellular organisms. RBP-Jκ is a downstream common transcriptional mediator in Notch signaling. The T cell specific deficiency of RBP-J□ resulted in selective loss of Th2 development. Distal 3' enhancer in Il4 locus that correlates with the conserved regions called, Conserved non-coding sequences (CNS)-2, contained multiple possible binding sites for RBP-Jκ. Using a transgenic GFP reporter system, we showed that binding of RBP-Jκ to the CNS-2 enhancer regulated initial IL-4 production from NKT cells and a subset of CD44^<hi> memory phenotype (MP) CD4 T cells. The Rbp-j deficient T cells exhibited marked reduction of both CNS-2 enhancer activity and initial IL-4 from NKT and MP CD4 T cells. Depletion of CNS-2 active CD4 T cells markedly decreased Th2 differentiation from naive CD4 T cells. These results indicate the functional importance of Notch signal and MP CD4 T cells in facilitating Th2 differentiation of naive CD4 T cells during initial stage of antigen induced allergic responses.

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 Acetaminophen-induced 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, R, Farrar, M.A, 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 signaling 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., Tanaki, 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 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 (in press)
• [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
  • Description: 「研究成果報告書概要(和文)」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., 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, 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(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 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(和文)」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(和文)」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: 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: 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, Abe, R, Yamamoto, M, Nohara, K
  • Journal Title: International Immunopharmacology 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, ubo, 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. Aller. 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: 8650-861
  • 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 THelper 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] Suppressor of Cytokine Signaling 3 (SOCS3) in the Th2 cells evoked Th2 cytokines, IgE and eosinophilia, (2006)
  • Author(s): Kubo, M., Inoue, H.
  • Journal Title: Current Allergy and Asthma Reports 9 Pages: 32-39
• [Journal Article] The interleukin-4 (IL-4) enhancer CNS-2 is regulated by Notch/RBP-J signals and cotrols initial IL-4 expression in NKT cells and memory-type CD4T 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
• [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): Watanabi, H., Kubo, M., Numata, K., Takagi, K., Mizuta, H., Okads, 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 (SOCK1) 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 CD8*+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