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MOLECULARANALYSIS ENDOTOXIN-INDUCED-DISEASES

Research Project

Project/Area Number 10470071
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Bacteriology (including Mycology)
Research InstitutionHYOGO COLLEGE OF MEDICINE

Principal Investigator

NAKANISHI Kenji  HYOGO COLLEGE OF MEDICINE, IMMUNOLOGY AND MEDICAL ZOOLOGY, PROFESSOR, 医学部, 教授 (60172350)

Co-Investigator(Kenkyū-buntansha) YOSHIMOTO Tomohiro  HYOGO COLLEGE OF MEDICINE, IMMUNOLOGY AND MEDICAL ZOOLOGY, ASSOCIATE PROFESSOR, 医学部, 助教授 (60241171)
TSUTSUI Hiroko  HYOGO COLLEGE OF MEDICINE, IMMUNOLOGY AND MEDICAL ZOOLOGY, ASSOCIATE PROFESSOR, 医学部, 助教授 (40236914)
OKAMURA Haruki  HYOGO COLLEGE OF MEDICINE, INSTITUTE FOR ADVANCED MEDICIAL SCIENCES, PROFESSOR, 医学部, 教授 (60111043)
AKIRA Shizuo  OSAKA UNIVERSITY, RESEARCHINSTITUTE FOR MICROBIAL DISEASES, PROFESSOR, 医学部, 教授 (50192919)
KASHIWAMURA Shin-ichiro  HYOGO COLLEGE OF MEDICINE, INSTITUTE FOR ADVANCED MADICAL SCIENCES, ASSISTANT PROFESSOR, 医学部, 講師 (00185761)
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥8,300,000 (Direct Cost: ¥8,300,000)
Fiscal Year 1999: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1998: ¥5,300,000 (Direct Cost: ¥5,300,000)
Keywordsinterleukin 18 / LPS-induced liver injury / caspase-1-deficient mice / IL-18-deficient mice / Fas ligand / 劇症肝炎 / caspase-1 / エンドトキシン / 肝炎 / IL-12 / IL-18 / FasL / TNF-α
Research Abstract

Murine IL-18 is constitutively produced and stored as a biologically inactive precursor, and pro-IL-18 is cleaved into biologically active mature IL-18 by enzymes that become active under proper stimulation. We studied pathological roles of IL-18 for LPS-induced liver injury. Mice subsequently treated with Propionibacterium acnes (P.acnes) and LPS suffer from liver injury. Coinjection of anti-IL-18 and LPS protects this liver. Furthermore, casapase-1 deficient(-/-) mice or IL-18-/- mice are resistant to this sequential treatments. These results strongly indicated the involvement of IL-18 in this LPS-induced liver injury. Indeed, injection of IL-18 instead of LPS also induced liver injury in P.acnes-pretreated mice. Since IL-18 induces IFN-γ, TNF and FasL either directly or indirectly, we assumed these molecules are responsible for inducing liver injury in these P.acnes-pretreated mice. Injection of FasL as a from of membrane bound (LNK cells) or soluble form induces liver injury in P.acnes-pretreated mice. Importantly, administration of soluble FasL induces acute liver injury in P.acnes-pretreated caspase-1 -/- mice but does not do so in P.acnes-pretreated IL-18 -/- mice, indicating the IL-18 release in a caspase-independent fashion is essential for this liver injury. Therefore, positive feedback loop between FasL and IL-18 plays an important role in pathogenesis of LPS liver injury.

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (30 results)

All Other

All Publications (30 results)

  • [Publications] Hayashi, N., et al.: "Kupffer cells from Schistosoma mansoni-infected mice participate in the prompt type 2-differentiation of hepatic T cells in response to worm antigens"J. Immunol.. 163. 6702-6711 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] kaisho, T., et al.: "Impairment of natural killer cytotoxic activity and interferon-γ production in C/EBPγ-deficient mice"J. Exp. Med.. 190. 1573-1581 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tsutsui, H., et al.: "Caspsae-1-independetnt, Fas/Fas ligand-mediated IL-18 secretion from macrophages causes acute liver injury in mice"Immunity. 11. 359-367 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Hyodo, Y., et al.: "Interleukin 18 upregulates perforin-mediated NK activity without increasing perforin messenger RNA expression by binding to constitutively expressed IL-18 receptor"J. Immunol.. 162. 1662-1668 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tsuji, H., et al.: "Alleviation of lipopolysaccharide-induced acute liver injury in Propionibacterium acnes-primed IFN-γ-deficient mice by a concomitant reduction of TNF-α, IL-12, and IL-18 production"J. Immunol.. 162. 1049-1055 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Sakao, Y., et al.: "IL18-deficient mice are resistant to endotoxin-induced liver injury but highly susceptible to endotoxin shock"Int. Immunol.. 11. 471-480 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 岡村春樹, 他: "エンドトキシン研究2 新しい展開(日本エンドトキシン研究会 編)"菜根出版. 7 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 松井 聖, 他: "エンドトキシン研究2 新しい展開(日本エンドトキシン研究会 編)"菜根出版. 7 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Hayashi, N., Matsui, K., Tsutsui, H., Osada, Y., Mohamed, R. T., Nakano, H., Kashiwamura, S-I., Hyodo, Y., Takeda, K., Akira, S., Hada, T., Higashino, K., Kojima, S., and Nakanishi, K.: "Kupffer cells from Schistosoma mansoni-infected mice participate in the prompt type 2-differentiation of hapatic T cell in response to worm antigens."J. Immunol. 163. 6702-6711 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kashio, T., Tsutsui, H., Tanaka, T., Tsujimura, T., Takeda, K., Kawai, T., Toshida, N., Nakanishi, K., and Akira, S.: "Impairment of natural killer cytotoxic activity and interfection-γ production in C/EBPγ-deficient mice."J. Exp. Med.. 190. 1573-1581 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tsutsui, H., Kayagaki, N., Kuida, k., Nakano, H., Hayashi, N., Takeda, K., Matsui, K., Kashiwamura, S-I., Hada, T., Akira, S., Yagita, H., Okamura, H. and Nakanishi, K.: "Caspase-1-independent , Fas/Fas ligand-mediated IL-18 secretion from macrophanges causes acute liver iujury on mice."Immunity. 11. 359-367 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Hyodo, Y., Matsui, K., Hayashi, N., Tsutsui, H., Kashiwamura, S-I., Yamauchi, H., Hiroishi, K., Takeda, K., Tagawa, Y., Iwakura, Y., Kayagaki, N., Kurimoto, M., Okamura, H., Hada, T., Yagita, H., Akira, S., Nakanishi, K and Higashino, K.: "Interleukin 18 upregulates perforin-mediated NK activity without increasing perforin messenger RNA expression by binding to constitutively expressed IL-18 receptor."J. Immunol.. 162. 1662-1668 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tsuji, H., Mukaida, N., Harada, A., Kaneko, S., Matsushita, E., Nakanuma, Y., Tsutsui, H., Okamura, H., Nakanishi, K., Tagawa, Y., Iwakura, Y., Kobayshi, K. and Matsushima, K.: "Alleviation of lipopolysaccharide-induced acute liver iujury in Propionibacterium acnes-primed IFN-γ-deficient mice by a concomitant redudtion of THF-α, IL-12, and IL-18 production."J. Immunol.. 162. 1049-1055 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Sakao, Y., Takeda, K., Tsutsui, H., Kaisho, T., Nomura, F., Okamura, H., Nakanishi, K. and Akira, S.: "IL18-deficient mice are resistant to endotoxin-induced liver iujury but highly susceptible to endotoxin shock."Int. Immunol.. 11. 471-480 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Hayashi,N.,et al.: "Kupffer cells from Schistosoma mansoni-infected mice participate in the prompt type 2-differentiation of hepatic T cells in response to worm antigens"J.Immunol.. 163. 6702-6711 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kaisho,T.,et al.: "Impairment of natural killer cytotoxic activity and interferon-γ production in C/EBP γ-deficient mice"J.Exp.Med.. 190. 1573-1581 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tsutsui,H.,et al.: "Caspase-1-independetnt, Fas/Fas ligand-mediated IL-18 secretion from macrophages causes acute liver injury in mice"Immunity. 11. 359-367 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hyodo,Y,et al.: "Interleukin 18 upregulates perforin-mediated NK activity without increasing perforin messenger RNA expression by binding to constitutively expressed IL-18 receptor"J.Immunol.. 162. 1662-1668 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tsuji,H.,et al.: "Alleviation of lipopolysaccharide-induced acute liver injury in Propionibacterium acnes-primed IFN-γ-deficient mice by a concomitant reduction of TNF-α,IL-12,and IL-18 production"J.Immunol.. 162. 1049-1055 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sakao,Y.,et al.: "IL18-deficient mice are resistant to endotoxin-induced liver injury but highly susceptible to endotoxin shock"Int.Immunol.. 11. 471-480 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 岡村春樹,他: "エンドトキシン研究2 新しい展開(日本エンドトキシン研究会 編)"菜根出版. 7 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 松井 聖,他: "エンドトキシン研究2 新しい展開(日本エンドトキシン研究会 編)"菜根出版. 7 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yoshimoto,T.et al.: "IL-12 up-regulates IL-18R expression on T cells,Thl cells and B cells:synergism with IL-18 for IFN-γ production." J.Immunol.161. 3400-3407 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yoshimoto,T.et al.: "LPS-stimulated SJL macrophages produce IL-12 and IL-18 that inhibit IgE production in vitro by induction of IFN-γ production from CD3^<int>IL-2R β^+T cells." J.Immunol.161. 1483-1492 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Adachi,O.et al.: "Tageted disruption of the MyD88 gene results in loss of IL-1-and IL-18-mediated function." Immunity.9. 143-150 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Takeda,K.et al.: "Defective NK cell activity and Thl response in IL-18-deficient mice." Immunity.8. 383-390 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tomura,M.et al.: "Diffential capacities of CD4^+,CD8^+ and CD4^. CD8^. T cell subsets to express IL-18 receptor and produce IFN-γ in response to IL-18." J.Immunol.160. 3759-3765 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tomura,M.et al.: "A critical role for interleukin-18 in the proliferation and activation of NK1.1^+CD3^. cells." J.Immunol.160. 4738-4746 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Okamura,H.et al.: "Adv.Immunol." Interleukin-18(IL-18):a novel cytokine that auguments both innate and acquired immunity., 32 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 善本知広,他: "Annu.Rev.免疫1999(菊池浩吉,矢田純一,奥村 康,編集)" サイトカイン:IL-18の生理機能, 13 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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