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Multiple organ dysfunction caused by cytokines, IL-12 and IL-18.-damages in the gland-

Research Project

Project/Area Number 11470045
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionHyogo College of Medicine

Principal Investigator

OKAMURA Haruki  Department of Medicine, Hyogo College of Medicine, Professor, 医学部, 教授 (60111043)

Co-Investigator(Kenkyū-buntansha) KASHIWAMURA Sinichiro  Department of Medicine, Hyogo College of Medicine, Assistant Professor, 医学部, 講師 (00185761)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥6,900,000 (Direct Cost: ¥6,900,000)
Fiscal Year 2000: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1999: ¥4,800,000 (Direct Cost: ¥4,800,000)
KeywordsNitric oxide / Interleukin18 / Interleukin12 / Lacrimal gland / 多臓器障害 / IL-12 / IL-18 / 活性酸素 / 腺組織 / アポトーシス
Research Abstract

IL-18 was discovered in 1995 as an IFN-γ-inducing factor in this institute. It is a cytokine with pleiotropic actions and now under vigorous investigation. IL-18 induces iNOS, COX-2, Fas ligand, and not only Th1 cytokines IFN-γ but Th2 cytokine such as IL-4, IL-5, and IL-13. The actions of IL-18 was reviewed by us in Ann.Rev.Immunol. (Annu.Rev.Immunol. 2001, 19 ; 423-474). IL-18 is profoundly involved in inflammatory reactions. And in the present study, we have shown that IL-18 in combination with IL-12 causes multiple organ dysfunction when administered to mice. When IL-12 and IL-18 were separately given to mice, they caused apparently no pathological changes, but when given in combination, they caused severe erosion in the intestine, atrophy in the thymus, fatty degeneration in the liver, and death in a few days. These cytokines failed to cause these pathological changes in IFN-γ-deficient mice, and induced milder changes in iNOS deficient mice. The change first appeared in the gland tissues and mumerous apoptotic cells were observed in the lacrimal gland. The administration of IL-12 and IL-18 failed to cause apoptotic changes in iNOS deficient mice. Various caspase inhibitors diminished the histological changes in the lacrimal gland. Thus, it was shown that IL-18 together with IL-12 is involved in the tissue damage through strong induction of IFN-γ. Moreover the down stream product, nitric oxide and reactive oxygen species were suggested to be directly responsible for the tissue damages. Thus IL-18 and IL-12 activate the destructive pathway by inducing IFN-γ, but recent studies revealed that IL-18 induces Th2 or anti-inflammatory cytokines such as IL-4, IL-5, and IL-13 in the absence of IL-12. Therefore, IL-18 may be involved also in the regulation of destructive pathway by inhibiting Th1 cytokines through induction of Th2 cytokines. Much remains to be clarified for this attractive cytokine.

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (32 results)

All Other

All Publications (32 results)

  • [Publications] Ohkusu,K.: "Potentiality of Interleukin-18 as a useful reagent for the treatmentand prevention of Leishmania major infection."Infect.Immunity.. 68. 2448-2456 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Fujimori,Y.: "Elevated interleukin (IL)-18 levels during acute graft-versus-host disease after allogeneic bone marrow transplantation."British.J.Haematology.. 109. 652-657 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Chikano,S.: "IL-18 and IL-12 induce intestinal inflammation and fatty liver in mice in an IFN-γ dependent manner."Gut.. 47. 779-786 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kodama,T.: "IL-18 deficiency selectively enhances allergen-induced eosinophilia in mice."J.allergy Clin.Immunol.. 105. 45-53 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shigehara,K.: "Increased levels of interleukin-18 in patients with pulmonary sarcoidosis."Am.J.Respir.Crit.Care.Med.. 162. 1979-1982 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kikkawa,S.: "A comparative analysis of the antigenic, structural, and functional properties of three different preparations of recombinant human interleukin-18."J.Interferon.Cytokine.Res.. 20. 179-185 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okamura,H.: "Academic Press."IL-18 receptor.. 5 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nakanishi,K.: "Annu.Rev.Immunol."Interleukin-18 regulates both Th1 and Th2 responses.. 5 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohkusu, K., et al.: "Potentiality of Interleukin-18 as a useful reagent for the treatment and prevention of Leishmania major infection."Infect.Immunity.. 68. 2448-2456 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Fujimori, Y., et al.: "Elevated interleukin (IL)-18 levels during acute graft-versus-host disease after allogeneic bone marrow transplantation."British.J.Haematology.. 109. 652-657 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Chikano, S., et al.: "IL-18 and IL-12 induce intestinal inflammation and fatty liver in mice in an IFN-γ dependent manner."Gut.. 47. 779-786 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kodama, T., et al.: "IL-18 deficiency selectively enhances allergen-induced eosinophilia in mice."J.allergy, Clin.Immunol.. 105. 45-53 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shigehara, K., et al.: "Increased levels of interleukin-18 in patients with pulmonary sarcoidosis."Am.J.Respir.Crit.Care.Med.. 162. 1979-1982 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kikkawa, S., et al.: "A comparative analysis of the antigenic, structural, and functional properties of three different preparations of recombinant human interleukin-18."J.Interferon.Cytokine.Res.. 20. 179-185 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okamura, H., et al.: "IL-18 receptor."The Cytokine Reference. Academic Press.. 5 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nakanishi, K., et al.: "Interleukin 18 regulates both Th1 and Th2 responses."Annual.Review.INC.Annu.Rev.Immunol.. 5 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohkusu,K.: "Potentiality of Interleukin-18 as a useful reagent for the treatmentand prevention of Leishmania major infection."Infect.Immunity.. 68. 2448-2456 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Fujimori,Y.: "Elevated interleukin (IL)-18 levels during acute graft-versus-host disease after allogeneic bone marrow transplantation."British.J.Haematology.. 109. 652-657 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Chikano,S.: "IL-18 and IL-12 induce intestinal inflammation and fatty liver in mice in an IFN-γ dependent manner."Gut.. 47. 779-786 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kodama,T.: "IL-18 deficiency selectively enhances allergen-induced eosinophilia in mice."J.allergy Clin.Immunol.. 105. 45-53 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Shigehara,K.: "Increased levels of interleukin-18 in patients with pulmonary sarcoidosis."Am.J.Respir.Crit.Care.Med.. 162. 1979-1982 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kikkawa,S.: "A comparative analysis of the antigenic, structural, and functional properties of three different preparations of recombinant human interleukin-18."J.Interferon.Cytokine.Res.. 20. 179-185 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Okamura,H.: "Academic Press."IL-18 receptor.. 5 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nakanishi,K.: "Annu.Rev.Immunol."Interleukin-18 regulates both Th1 and Th2 responses.. 5 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sakao,Y.: "IL 18-deficient mice are resistant to endotoxin-induced liver injury but highly susceptible to endotoxin shock"International Immunology. 11. 471-480 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kawakami,K.: "Role of TNF-alpha in the induction of fungicidal activity of mouse peritoneal exudate cells against Cryptococcus neoformans by IL-12 and IL-18"Cellular Immunology. 10. 9-16 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tsutsui,H.: "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] Rothe,H.: "IL-18 inhibits diabetes development in nonobese diabetic mice by couterregulation of Th1-dependent destructive insulitis"Jouranal of Immunolgy. 163. 1230-1236 (1999)

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

    • Related Report
      1999 Annual Research Report
  • [Publications] Osaki,T.: "Potent antitumor effects mediated by local expression of the mature form of the interferon-gamma inducing factor,interleukin-18(IL-18)"Gene Therapy. 6. 808-815 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 岡村春樹: "エンドトキシンとIL-18、エンドトキシン研究2 新しい展開"菜根出版,(東京). 7 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 松井 聖: "エンドトキシン肝障害における肝内リンパ球とIL-18の役割,エンドトキシン研究2 新しい展開"菜根出版,(東京). 7 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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