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Functional analysis of IL-1 in immune and stress responses using gene knockout mice

Research Project

Project/Area Number 10670298
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Immunology
Research InstitutionKanazawa University (2000-2001)
The University of Tokyo (1998-1999)

Principal Investigator

ASANO Masahide  Kanazawa Univ., Faculty of Medicine, Professor, 医学部, 教授 (50251450)

Co-Investigator(Kenkyū-buntansha) HASHIMOTO Noriyoshi  Kanazawa Univ., Faculty of Medicine, Research Associate, 医学部, 助手 (50242524)
SUDO Katsuko  Tokyo Univ., Inst. Med. Sci., Research Associate, 医科学研究所, 助手 (50126091)
IWAKURA Yoichiro  Tokyo Univ., Inst. Med. Sci., Professor, 医科学研究所, 教授 (10089120)
Project Period (FY) 1998 – 2000
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2000: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1999: ¥700,000 (Direct Cost: ¥700,000)
KeywordsIL-1 / Knockout mice / Inflammation / Antibody Production / Contact Hypersensitivity / RheumatoidArthritis / Stress Response / Apoptosis / T細胞フライミング / 細菌誘導性肝炎 / ディファレンシャル・ディスプレイ / エンドトキシンショック
Research Abstract

IL-1 α, IL-1 β, IL-Ira KO and IL-1 α/β double KO mice were generated to elucidate pleiotropic function of IL-1 in an animal body, and roles of IL-1 in immune and stress responses were clarified as described below.
(1) IL-1 β , but not IL-1 α, is crucial in terpentine-induced fever development and glucocorticoid secretion.
(2) Inflammation induced by apoptosis inducer Fas ligand is mediated by IL-1 β which is released by caspase 1 independent mechanism.
(3) Chronic inflammatory arthropathy resembling rheumatoid arthritis is spontaneously developed in IL-Ira KO mice on a BALB/c background.
(4) LPS-induced HIV-1 expression in transgenic mice is mediated by TNF α and IL-1.
(5) In collaboration with other laboratories, apoptosis in neural cells caused by ischaemia and apoptosis in germ cells caused by loss of ataxia telangiectasia-mutated (Atm) gene function are mediated by IL-1β.
(6) T cell-dependent antibody production is regulated by IL-1 β, but not by IL-1 α, through induction of CD40L and OX40 on T cells.
(7) IL-1α, but not IL-1β, is required for contact-allergen-specific T cell activation during the sensitization phase in contact hypersensitivity.
(8) Suppression of autoimmune arthritis in IL-1 KO mice in which T cell activation is impaired due to low levels of CD40 ligand and OX40 expression on T cells.
In support with the Grant-in-Aid for Scientific Research, various roles of IL-1 in fever development, stress response, antibody production, contact hypersensitivity, rheumatoid arthritis development and apoptosis of neural cells and germ cells were elucidated. These results and our IL-1 genes KO mice could be very useful to understand the mechanism of IL-1-mediated human diseases and to develop medical treatment for them.

Report

(4 results)
  • 2001 Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (47 results)

All Other

All Publications (47 results)

  • [Publications] Horai, R., et al.: "Production of mice deficient in genes for IL-1α IL-1β IL-1α/β and IL-1 receptor antagonist shows that IL-1β is crucial in turpentine-induced fever development and glucocorticoid secretion"Journal of Experimental Medicine. 187. 1463-1475 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Miwa, K., et al.: "Caspase 1-independent IL-1β release and inflammation induced by the apoptosis inducer Fas ligand"Nature Medicine. 4. 1287-1292 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Horai, R., et al.: "Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in IL-1 receptor antagonist-deficient mice"Journal of Experimental Medicine. 191. 313-320 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanaka, J., et al.: "Lipopolysaccharide-induced HIV-1 expression in transgenic mice is mediated by tumo necrosis factor-α and interleukin-1, but not by interferon-γ nor interleukin-6"AIDS. 14. 1299-1307 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Boutin, H., et al.: "Role of IL-1α and IL-1β in ischaemic brain"Journal of Neuroscience. 21. 5528-5534 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakae, S., et al.: "IL-1 enhances T cell-dependent antibody production through induction of CD40L and OX40 on T cells"Journal of Immunology. 167. 90-97 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Morita, Y, et al.: "Caspase-2 deficiency prevents programmed gern cell death resulting from oytokine insufficiency bu not meiotic defects caused by loss of ataxia telangiectasia-mutated (Atm) gene function"Cell Death and Differentiation. 8. 614-620 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Imaizumi, Y., et al.: "Increased expression of interleukin-1β in mouse hippocampus after global cerebral ischemia"Acta. Histochem. Cytoochem.. 34. 357-362 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakae, S., et al.: "IL-1α, but not IL-1β, is required for contact-allergen-specific T cell activation during the sensitization phase in contact hypersensitivity"International Immunology. 13. 1471-1478 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakae, S., et al.: "Interleukin-1β, but not Interleukin-1α, is required for T cell-dependent antibody production"Immunology. 104. 402-409 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Saijo, S., et al.: "Suppression of autoimmune arthritis in interleukin-1-deficient mice in which T cell activation is impaired due to low levels of CD40 ligand and OX40 expression on T cells"Arthritis and Rheumatism. 46. 533-544 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Horai, R., Asano, M., Sudo, K., Kanuka, H., Suzuki, M., Nishihara, M., Takahashi, M. and Iwakura, Y: "Production of mice deficient in genes for IL-lα, IL-1β, IL-lα/β, and IL-1 receptor antagonist shows that IL-1β is crucial in turpentine: induced fever development and glucocorticoid secretion"J. Exp. Med.. 187. 1463-1475 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Miwa, K., Asano, M., Horai, R., Iwakura, Y., Nagata, S. and Suda, T.: "Caspase 1-independent IL-1β release and inflammation induced by the apoptosis inducer Fas ligand"Nature Med. 4. 1287-1292 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Horai, R., Saijo, S., Tanioka, H., Nakae, S., Sudo, K., Okahara, A., Ikuse, T., Asano,M. and Iwakura, Y: "Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in IL-1 receptor antagonist-deficient mice"J. Exp Med. 191. 313-320 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tanaka, J., Ozaki, H., Yasuda, J., Horai, R., Tagawa, Y., Asano, M., Saijo, S., Imai, M., Sekikawa, K., Kopf, M., Iwakura Y: "Lipopolysaccharide-induced HIV-1 expression in transgenic mice is mediated by tumor necrosis factor-α and interleukin-1, but not by interferon-γ nor mterleukin-6"AIDS. 14. 1299-1307 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Boutin, H., LeFeuvre, R.A., Smith, C, Horai, R., Asano, M., Iwakura, Y. and Rothwell, N.J: "Role of IL-lα and IL-1β in ischaemic brain"J.Neuroscience. 21. 5528-5534 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakae, S., Asano, M., Horai, R., Sakaguchi N. and Iwakura Y.: "lL-1 enhances T cell-dependent antibody production through induction of CD40L and OX40 on T cells"J.Immunol.. 167. 90-97 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Morita, Y., Maravei, D.V., Bergeron, L., Wang, S., Perez G.I., Tsutsumi, 0., Taketani, Y., Asano, M., Horai, R., Korsmeyer, S.J., Iwakura, Y., Yuan, J. and Tilly, J.L.: "Caspase-2 deficiency prevents programmed germ cell death resulting from cytokine insufficiency but not meiotic defects caused by loss of ataxia telangiectasia-mutated (Aim) g function"Cell Death Differ. 8. 614-620 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Imaizumi, Y., Mizushima, H., Matsumoto, H., Dohi, K., Matsumoto, K., Ohtaki, H., Funahashi, H., Matsunaga, S., Horai, R., Asano, M, Iwakura, Y. and Shioda, S.: "Increased expression of interleukin-1β in mouse hippocampus after global cerebral ischemia"Acta. Histochem. Cytochem. 34. 357-362 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakae, S., Naruse-Nakajima/C, Sudo, K., Horai, R., Asano, M. and Iwakura, Y: "IL-lα, but not IL-1β, is required for contact-allergen-specific T cell activation during the sensitization phase in contact hypersensitivity"Int. Immunol.. 13. 1471-1478 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakae, S., Naruse-Nakajima/C, Sudo, K., Horai, R., Asano, M. and Iwakura, Y: "Interleukin(IL)-1β, but not IL-1α, is required for T cell-dependent antibody production"Immunology. 104. 402-409 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Saijo, S. Asano M., Horai, R., Yamamoto, H. and Iwakura, Y: "Suppression of autoimmune arthritis in interleukin-1-deficient mice in which T cell activation is impaired due to low levels of CD40 ligand and OX40 expression on T cells"Arth. Rheum.. 46. 533-544 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Naruse,C., et al.: "Eph-A2 mutant mice revealed Eph-A2 and ephrin-A1 are involved in formation of the tail notochord"Mech.Dev. In press. (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Serizawa,S., et al.: "Mutually exclusive expression of odorant receptor transgenes"Nature Neurosci.. 3. 687-693 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tanaka,J., et al.: "Lipopolysaccharide-induced HIV-1 expression in transgenic mice is mediated by tumor necrosis factor-α and interleukin-1, but not by interferon-γ nor interleukin-6"AIDS. 14. 1299-1307 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hayashi,K., et al.: "Diminution of the AML1 transcription factor function causes differential effects on the fates of CD4 and CD8 single positive T cells"J.Immunol.. 165. 6816-6824 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kido,M., et al.: "Presence of a higher molecular weight β-1,4-galactosyltransferase in mouse liver"Acta Histochem.Cytochem.. 33. 215-221 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Uetani,N., et al.: "Impaired learning with enhanced hippocampal long-term potentiation in PTP-δ-deficient mice"EMBO J.. 19. 2775-2785 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Horai,R.,et al.: "Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in IL-1 receptor antagonist-deficient mice"J. Exp. Med.. 191. 313-320 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kido,M.,et al.: "Normal levels of serum glyoproteins maintained in β-1,4-galactosyltransferase I -knockout mice"FEBS Letters. 464. 75-79 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Asano,M.,et al.: "Roles of IL-1 and TNF-α in varioius inflammations"J. Interferon Cytokine Res.. 19. S60 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kotani,N.,et al.: "Impaired galactosylation of core 2 O-glycans in erythrocytes of β1,4-galactosyltransferase"Biochem. Biophys. Res. Commun.. 260. 94-98 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Habu,K.,et al.: "The HTLV-I-tax gene is responsible for the development of both inflammatory arthropathy resembling rheumatoid arthritis and non-inflammatory ankylotic arthropathy in transgenic mice"J. Immunol.. 162. 2956-2963 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Horai,R.et al.: "Production of mice deficient in genes for IL-1α,IL-1β,IL-1α/β,and IL-1 ra shows that IL-1β is cruciao in turpentine-induced fever development" J.Exp.Med.187. 1463-1475 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Iwakura,Y.,et al: "The development of autoimmure arthropathy in mice transgenio for the HTLV-I env-pX region is not dependent on H-2 haplotypes and modiliod by Fasciatrgen" J.Immunol.161. 6592-6598 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kotani,M.et al.: "Involvement of Autoimmunity.Against typell collgen in the development of arthritis in mice transgenic for the HTLV-I taxgene" Eur.J.Immunol.29. 54-64 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Habu,K.,et al: "The HTLV-I-taxgene is respansible for the development of both infroinna-tory polyarthropathy and non-inflamma tory ankyloticarthropathy in transgenic in cp." J.Immural. (in press).

    • Related Report
      1998 Annual Research Report
  • [Publications] Flamand,V.et al: "CD40 ligation prevents neonatal induction of transplan tation to lerancl." J.Immunol. 160. 4666-4669 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kyuwa,S.et al: "Murine coronaviras-induced subacute fatal pri tonitis in C573L/6 mice deficient in gamma interferon" J.Virol.72. 9286-9290 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kyuwa,S.et al: "MHV-induced fatal peritonitis in mice lacking IFN-r." Adv.Exp.Med.Biol. 440. 445-450 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Miwa,K. et al.: "Caspasel-independent IL-1β release and inflammatiorinduced by the apoptosis inducer Fas ligand." Nat.Med.4. 1287-1292 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kido,M.et al: "Presence of polysialic acid and HNK-1 carloohydrate on brain glycopro teins from β-1,4 galT-krockout mice" Biochem.Biophys.Res.Commun. 245. 860-864 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sugawara,I.et al.: "Induction of granulomas in interferon-r gene-disrupted mice by aviralent but not by virulent strain of Mycobactenum tuberavosis" J.Med.Microbiol.47. 871-877 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tagawa,Y.et al.: "Involvement of Fas/Fas ligard system-mediated apoptosis in the development of ConA-induced hepatitis." Enr.J.Immunol.28. 4105-4113 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tsuji,H.et al.: "Alleviation of LPS-induced acuteliver injury in P.ac nes-primed IENir-deficient mice by a Concomitant reduceon of TNF α,IL-12 and IL-18 production" J.Immunol.162. 1049-1055 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Hyodo,Y.et al.: "IL-18 upregutates exocytosis-mediated NK actrvity without affecting porforin mRNA expression by binding to constitulively expressed IL-18R." J.Immunol. 162. 8662-8668 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sawai,N.et al: "Pole of gammainterferon in Hlicobacter pylori-induced gastric inflammatory responses in a mouse medel." Infect.Immun.67. 279-285 (1999)

    • Related Report
      1998 Annual Research Report

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

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