• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Analysis of IL-18 signaling pathways accounting for its various biological actions

Research Project

Project/Area Number 13670485
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 内科学一般
Research InstitutionHYOGO COLLEGE OF MEDICINE

Principal Investigator

TSUTSUI Hiroko  HYOGO COLLEGE OF MEDICINE, IMMUNOLOGY AND MEDICAL ZOOLOGY, Associate Professor, 医学部, 助教授 (40236914)

Co-Investigator(Kenkyū-buntansha) OKAMURA Haruki  HYOGO COLLEGE OF MEDICINE, INSTITUTE FOR ADVANCED MEDICAL SCIENCES, Professor, 医学部, 教授 (60111043)
NAKANISHI Kenji  HYOGO COLLEGE OF MEDICINE, IMMUNOLOGY AND MEDICAL ZOOLOGY, Professor, 医学部, 教授 (60172350)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2001: ¥2,500,000 (Direct Cost: ¥2,500,000)
KeywordsInterleukin-18 / Th1 cytokines / Th2 cytokines / NK activity / MyD88 / Tyk2 / IL-18 receptor / CD4^+ T cells / TH1サイトカイン / TH2サイトカイン / CD4+ cells / インターロイキン18 / インターフェロンγ / 炎症 / アレルギー / シグナル伝達系 / ノックアウトマウス
Research Abstract

IL-18 is a pleiotropic cytokine secreted upon activation of innate immunity. In combination with IL-12, IL-18 induces Th1-related cytokines such as IFN-g from various types of cells including NK cells, CD4+ T cells and dendritic cells. Together with IL-2, IL-18 renders naive CD4+ T cells to produce Th2-related cytokines, such as IL-4 and IL-13. Furthermore, IL-18 plus IL-3 triggers IL-4 and IL-13 production and histamine release by basophils and mast cells without cross-linkage of their FcεR. IL-18 solely activates NK cells, to produce IFN-γ and to augment their NK activity. Therefore, IL-18 appears to be involved in various immunopathological alterations such as inflammatory diseases, hyper IgE syndrome and allergic disorders. Here, we investigated the molecular mechanisms underlying IL-18-induced various biological events, particularly focusing on IL-1-medtated signal pathway because of homology of intracellular domain of receptors between IL-1 and IL-18. Mutant mice tacking myeloid differentiation factor 88, an intracellular signal adaptor essential for IL-1 signaling, showed impairment in activation of NK cells and IFN-γ production in the presence of IL-12 upon stimulation with IL-18. Next, we tested possible involvement of tyk2 in IL-18 signal pathways, because tyk2 was demonstrated to be required for IL-12 that up-regulates IL-18R expression on T cells and NK cells. Tyk2-deficient NK cells did not produce IFN-γ or IL-13, or increase in its cytotoxicity against NK-sensitive target cells in response to IL-18. Tyk2-deficient CD4^+ T cells did not produce IFN-γ or IL-4/IL-13 in response to IL-12 plus IL-18 and IL-2 plus IL-18, respectively. These results suggested that tyk2 is important for these IL-18 actions, although tyk2 is a member of JAK kinase family and involved in stat-mediated signalings, which is believed not to be involved in IL-18 signal pathways.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (60 results)

All Other

All Publications (60 results)

  • [Publications] Seki, E., Tsutsui, H., et al.: "Lipopolysaccharide-induced IL-18 secretion from murine Kupffer cells independently of Myeloid differentiation factor 88 that is critically involved in induction of production of IL-12 and IL-1β"J. Immunol.. 166. 2651-2657 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Naka, T., Tsutsui, H., et al.: "SOCS (suppressor of cytokine signaling)-/SSI(stat-induced stat inhibitor)-1-deficient hepatic NKT cells participate in severe hepatits through dysregulated cross-talk inhibition of IFN-g and IL-4 signaling"Immunity. 14. 535-545 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Itoi, H., Fujimori, T., Tsutsui, H., et al.: "Fas ligand-induced, caspase-1-dependent accumulation of interleukin (IL)-18 in mice with acute graft-versus-host disease"Blood. 98. 235-237 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tanaka, T., Tsutsui, H., et al.: "Interleukin-18 is elevated in the sera from patients with atopic dermatitis and from atopic dermatitis model mice, NC/Nga."Int. Arc. Allergy Immunol.. 125. 236-240 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Adachi, K., Tsutsui, H., et al.: "Plasmodium berghei infection in mice induces liver injury by an IL-12-and Toll-like receptor/myeloid differentiation factor 88-dependent mechanism"J. Immunol.. 167. 5928-5934 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Iwasaki, T., Yamashita, K., Tsujimura, T., Kashiwamura, S., Tsutsui, H., et al.: "Interleukin-18 inhibits osteolytic bone metastasis by human lung cancer cells possibly through suppression of osteoclastic bone-resorption in nude mice"J. Immunotherapy. 25. S52-S60 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shimoda, K., Tsutsui, H., et al.: "Partial impairment of IL-12 and IL-18 signaling in Tyk2-deficient mice"Blood. 99. 2094-2099 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Konishi, H., Tsutsui, H., et al.: "IL-18 contributes to the development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions"Proc. Natl. Acad. Sci. USA. 99. 11340-11345 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fujimori, T, et al.: "Increased expression of interleukin 18 receptor on T lymphocytes in patients with acute graft-versus-host disease after allogeneic bone marrow transplantation"J. Interferon Cytokine Res.. 22. 751-754 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Seki, E., Tsutsui, H., et al.: "Critical roles of MyD88-dependent proinflammatory cytokine release in early phase clearance of Listeria monocytogenes"J. Immunol.. 169. 3863-3868 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fujimoto, M., Tsutsui, H., et al.: "A regulatory role for suppressor of cytokine signaling-1 in Th polarization in vivo"Int. Immunol.. 14. 1343-1350 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakagawa, R., Naka, T., Tsutsui, H., et al.: "SOCS-1 participates in negative regulation of LPS responses"Immunity. 17. 677-687 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakano, H., Tsutsui, H., et al.: "Persistent secretion of IL-18 in the skin contributes to IgE response in mice"Int. Immunol.. 15(In press). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakamoto, y., Kaneko, S., Fan, H., Momooi, T., Tsutsui, H., et al.: "Prevention of hepatocellular carcinoma development associated with chronic hepatitis by anti-Fas ligand antibody therapy"J. Exp. Med.. 196. 1105-1111 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hayashi, h., Inoue, Y., Tsutsui, H., et al.: "TGFβ down-regulates IFN-γ production in IL-18-treated NK cell line LNK5E6 cells"Biochem. Biophys. Res. Commun.. 300. 980-985 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakanishi, K., Yoshimoto, T., Tsutsui, H., Okamura, H.: "Annu. Rev. Immunol."Annual Reviews, Inc. 839 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 筒井ひろ子, 中西憲司: "免疫学コア講義(木本雅夫, 阪口薫雄, 山下優毅 編)"南山堂. 335 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Seki, E., Tsutsui, H., et al.: "Lipopolysaccharide-induced IL-18 secretion from murine Kupffer cells independently of myeloid differentiation factor 88 that is critically involved in induction of production of IL-12 and IL-1β"J.Immunol.. 166. 2651-2657 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Naka, T., Tsutsui, H., et al.: "SOCS (suppressor of cytokine signaling)-/SSI (stat-induced stat inhibitor)-1-deficient hepatic NKT cells participate in severe hepatitis through dysregulated cross-talk inhibition of IFN-γ and IL-4"Immunity. 14. 535-545 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Itoi, H., Fujimori, T., Tsutsui, H., et al.: "Fas ligand-induced, caspase-1-dependent accumulation of interleukin (IL)-18 in mice with acute graft-versus-host disease"Blood. 98. 235-237 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tanaka, T., Tsutsui, H., et al.: "Interteukin-18 is elevated in the sera from patients with atopic dermatitis and from atopic dermatitis model mice, NC/Nga"Int.Arc.Allergy Immunol.. 125. 236-240 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Adachi, K., Tsutsui, H., et al.: "Plasmodium berghei infection in mice induces liver injury by an iL-12- and Toll-like receptor/myeloid differentiation factor 88-dependent mechanism"J.Immunol.. 167. 5928-5934 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Iwasaki, T., et al.: "Interleukin-18 inhibits osteolytic bone metastasis by human lung cancer cells possibly through suppression of osteoclastic bone-resorption in nude mice"J.Immunotherapy. 25. S52-S60 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakanishi, K., et al.: "Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu"Cytokine and Growth Factor Rev.. 12. 53-72 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakanishi, K., et al.: "Interleukin-18 regulates both Th1 and Th2 responses"Annu.Rev.Immunol.. 19. 423-474 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shimoda, K., Tsutsui, H., et al.: "Partial impairment of IL-12 and IL-18 signaling in Tyk2-deficient mice"Blood. 99. 2094-2099 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Konishi, h., Tsutsui, H., et al.: "IL-18 contributes to the development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions"Proc.Natl.Acad.Sci.USA. 99. 11340-11345 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fujimori, T., et al.: "Increased expression of interleukin 18 receptor on T lymphocytes in patients with acute graft-versus-host disease after allogeneic bone marrow transplantation"J.Interferan Cytokine Res.. 22. 751-754 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Seki, E., Tsutsui, H., et al.: "Critical roles of MyD88-dependent proinflammatory cytokine release in early phase clearance of Listeria monocytogenes"J.Immunol.. 169. 3863-3868 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fujimoto, M., Tsutsui, H., et al.: "A regulatory role for suppressor of cytokine signaling-a in Th1 polarization, in vivo"Int.Immunol.. 14. 1343-1350 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakagawa, R., Naka, T., Tsutsui H., et al.: "SOCS-1 participates in negative regulation of LPS responses"Immunity. 17. 677-687 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakamoto, Y., et al.: "Prevention of hepatocellular carcinoma development associated with chronic hepatitis by anti-Fas ligand antibody"J.Exp.Med.. 196. 1105-1111 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hayashi, H., Inoue, Y., Tsutsui, H., et al.: "TGF-β down regulates IFN-γ production in IL-18 treated NK cell line LNK5E6 cells"Biochem.Bioophys.Res.Commun.. 300. 980-985 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakano, H., Tsutsui, H., et al.: "Persistent secretion of IL-18 in the skin contributes to IgE response in mice"Int.Immunol.. 15(In press). (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Seki, E., Tsutsui, H., et al.: "Lipopolysaccharide-induced IL-18 secretion from murine Kupffer cells independently of Myeloid differentiation factor 88 that is critically involved in induction of production of IL-12 and IL-1β"J. Immunol.. 166. 2654-2657 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Naka, T., Tsutsui, H., et al.: "SOCS (suppressor of cytokine signaling)-/SSI(stat-induced stat inhibitor)-1-deficient hepatic NKT cells participate in severe hepatits through dysregulated cross-talk inhibition of IFN-g and IL-4 signaling"Immunity. 14. 535-545 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Itoi, H., Fujimori, T., Tsutsui, H., et al.: "Fas ligand-induced, caspase-1-dependent accumulation of interleukin (IL)-18 in mice with acute graft-versus-host disease"Blood. 98. 235-237 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tanaka, T., Tsutsui, H., et al.: "Interleukin-18 is elevated in the sera from patients with atopic dermatitis and from atopic dermatitis model mice, NC/Nga"Int. Arc. Allergy Immunol.. 125. 236-240 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Adachi, K., Tsutsui, H., et al.: "Plasmodium berghei infection in mice induces liver injury by an IL-12-and Toll-like receptor/myeloid differentiation factor 88-dependent mechanism"J. Immunol.. 167. 5928-5934 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Iwasaki, T., Yamashita, K., Tsujimura, T., Kashiwamura, S., Tsutsui, H., et al.: "Interleukin-18 inhibits osteolytic bone metastasis by human lung cancer cells possibly through suppression of osteoclastic bone-resorption in nude mice"J. Immunotherapy. 25. S52-S60 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shimoda, K., Tsutsui, H., et al.: "Partial impairment of IL-12 and IL-18 signaling in Tyk2-deficient mice"Blood. 99. 2094-2099 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Konishi, H., Tsutsui, H., et al.: "IL-18 contributes to the development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions"Proc. Nati. Acad. Sci. USA. 99. 11340-11345 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Fujimori, T, et al.: "Increased expression of interleukin 18 receptor on T lymphocytes in patients with acute graft-versus-host disease after allogeneic bone marrow transplantation"J. Interferon Cytokine Res.. 22. 751-754 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Seki, E., Tsutsui, H., et al.: "Critical roles of MyD88-dependent proinflammatory cytokine release in early phase clearance of Listeria monocyto genes"J. Immunol.. 169. 3863-3868 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Fujimoto, M., Tsutsui, H., et al.: "A regulatory role for suppressor of cytokine signaling-1 in Th polarization in vivo"Int. Immunol.. 14. 1343-1350 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nakagawa, R., Naka, T., Tsutsui, H., et al.: "SOCS-1 participates in negative regulation of LPS responses"Immunity. 17. 677-687 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nakano, H., Tsutsui, H., et al.: "Persistent secretion of IL-18 in the skin contributes to IgE response in mice"Int. Immunol.. 15(In Press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nakamoto, y., Kaneko, S., Fan, H., Momooi, T., Tsutsui, H., et al.: "Prevention of hepatocellular carcinoma development associated with chronic hepatitis by anti-Fas ligand antibody therapy"J. Exp. Med.. 196. 1105-1111 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nakanishi, K., Yoshimoto, T., Tsutsui, H., Okamura, H.: "Annu. Rev. Immunol."Annual Reviews, Inc. 839 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] 筒井ひろ子, 中西憲司: "免疫学コア講義(木本雅夫,阪口薫雄,山下優毅 編)"南山堂. 335 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Seki, E., et al.: "Lipopolysaccharide-induced IL-18 secretion from murine Kupffer Cells independently of Myeloid Differentiation Factor 88 That is critically involved in induction of production of IL-12 and IL-1beta"Journal of Immunology. 166. 2651-2657 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Itoi, H., et al.: "Fas ligand-induced caspase-1-dependent accumulation of interleukin-18 in mice with acute graft-versus-host disease"Blood. 98. 235-237 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Naka, T., et al.: "SOCS(Suppressor of Cytokine Signaling) -ISSI(STAT-induced STAT Inhibitor)-1-deficient hepatu participate in severe hepatitis through dysregulated cross-talk inhibition of IFN-γ and IL-4 signaling in vivo"Immunity. 13. 535-545 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Adochi, K., et al.: "Plasmodium berghei infection in mice induces liver injury by an IL-12-and toll-like receptor/myeloid differentiation factor 88-dependent mechanism"Journal of Immunology. 167. 5928-5934 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tanaka, T., et al.: "Interleukin-18 is elevated in the sera from patients with atopic dermatitis and from atopic dermatitis-model mice, NC/Nga"International Archtectone of Allergy and Immunology. 125. 236-240 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shimada, K., et al.: "Partial impairment of IL-12 and IL-18 signaling in Tyk2-deficient mice"Blood. (In press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nakanishi, K., et al.: "Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu"Cytokine and Grouth Factor Review. 12. 53-72 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nakanishi, K., et al.: "Interleukin-18 regulates both Th1 and Th2 responses"Annual Review in Immunology. 19. 423-474 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tsutsui, H., et al.: "Encyclopedia Hormones"Academic press (In press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yoshimoto, T., et al.: "Carrent Protocol in Immunology"John Wiley & Sons.Inc. 12 (2001)

    • Related Report
      2001 Annual Research Report

URL: 

Published: 2001-04-01   Modified: 2016-04-21  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi