Development of therapeutic strategy for allergic disorder on the basis of genome informations

2004 Fiscal Year Final Research Report Summary

• Project/Area Number: 14370165
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 内科学一般
• Research Institution: RIKEN (2004); Tokyo University of Science (2002-2003)
• Principal Investigator: KUBO Masato RIKEN Yokohama Institute, Laboratory for Signal Network, Laboratory head, 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): KOUYAMA Masako Tokyo University of Science, Research associate, 生命科学研究所, 助手 (80318229) ; HAYASHI Katsuhiko Research Institutes, Osaka Medical Center for Maternal and Child Health, Department of Molecular Embryology, Research scientist, 病因病態部門, 常勤研究員 (20287486) ; SEKI Yoh-ichi Japan Society for the Promotion of Science, Post-doctoral Fellows, 生命科学研究所・分子生物学研究部門, 学術振興会特別研究員
• Project Period (FY): 2002 – 2004
• Keywords: Cytokine signal / Effector T cell differentiation / Th1 / Th2 / IL-4 / chromatin / epileptics

Research Abstract

After the advanced economic growth, allergic disease, such as pollinosis, asthma and Atopic dermatitis, seriously become social problem in urban area of Japan. Although a steroid and immunosuppressant agent are so far commonly used for the therapeutic treatment of allergic patients, these treatment carried on the harmful side effect in some case, thus the development of novel therapeutic strategy to function more than the side effect would be necessary in the future. We focus on Th2 developmental process as therapeutic target for allergic disease.
An initial activation signal via the T cell antigen receptor(TCR) in a restricted cytokine environment is critical for the onset of helper T(Th) cell development. Cytokines regulate the expression of key transcriptional factors, T-bet and GATA-3,which instruct the direction of Th1 and Th2 differentiation, through changes in chromatin conformation. In this study, we investigated the kinetics of IL-4-mediated signaling in a transgenic mouse, exp ressing human IL-4 receptor (hIL-4R Tg) on a mouse IL-4 receptor deficient background. These experiments demonstrated that an IL-4 signal was required at the early stage of TCR mediated T cell activation for lineage commitment to Th2, along with structural change in chromatin, in conserved non-coding sequences (CNS)-1 and -2 within the IL-4 locus.
Epigenetic changes in the chromatin structure of the Th2 locus tightly associate with cytokine expression profile during the differentiation process from naive CD4 T cells to effecter Th2 cells. Using a transgenic approach, we studied cis-acting activity of considerable conservation of noncording sequences on II4 locus. CNS-2 corresponding to Th2 specific-remodeling site located at downstream of II4 gene, regulated the primary IL-4 production in CD62L^<lo> CD44^<hi> memory like CD4^+ T cells. The depletion of the CNS-2-regulated T cells resulted complete loss of Th2 differentiation. This CNS-2 contains putative binding site for RBP-J, which is a critical modulator for Notch signaling. CD4 T cell specific RBP-J deficient mice showed abrogation of primary IL-4 production from the memory like T cells and Th2 development. Therefore, Notch/RBP-J signaling mediated CNS-2 regulation is a crucial for primary IL-4 production in Th2 differentiation.

Research Products

• [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
  • Description: 「研究成果報告書概要(和文)」より
• [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
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The Runx1 transcription factor Inhibits the differentiation of naive CD4^+ T Cells into the Th2 lineage by repressing GATA3 expression. (2003)
  • 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
  • Description: 「研究成果報告書概要(和文)」より
• [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
  • Description: 「研究成果報告書概要(和文)」より
• [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., KatoS., Tsukada, J., Nomura, Y., Mimata, H., Kubo, M., Yoshimura, A.
  • Journal Title: Immunity 19, 9 Pages: 437-450
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Suppressor of cytokine signaling and immunity (2003)
  • Author(s): Kubo, N., Hanada, T, Yoshimura, A.
  • Journal Title: Nature Immunology 4, 12 Pages: 1169-1176
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The Runx1 transcription factor Inhibits the differentiation of naive CD4^+ T Cells into the Th2 lineage by repressing GATA3 expression. (2003)
  • 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 Pages: 51-61
  • Description: 「研究成果報告書概要(欧文)」より
• [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
  • Description: 「研究成果報告書概要(欧文)」より
• [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
  • Description: 「研究成果報告書概要(欧文)」より
• [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
  • Description: 「研究成果報告書概要(欧文)」より
• [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
  • Description: 「研究成果報告書概要(和文)」より