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Analysis of the function of membrane TNF-α

Research Project

Project/Area Number 14570418
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 内科学一般
Research InstitutionKyushu University

Principal Investigator

HORIUCHI Takahiko  Kyushu University Hospital, Assistant Professor, 大学病院, 講師 (90219212)

Co-Investigator(Kenkyū-buntansha) TSUKAMOTO Hiroshi  Kyushu University Hospital, Research Associate, 大学病院, 助手 (70304772)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
Keywordscytokine / anti-TNF-αtherapy / Crohn's disease / Rheumatoid arthritis / アポトーシス
Research Abstract

TNF-□ antagonists are the. center of attention for their dramatic clinical efficacy in active chronic inflammatory diseases. In rheumatoid arthritis, both infliximab (chimeric anti-TNF-□ antibody) and etanercept(p75 TNF-□ receptor fusion protein) are highly effective while in Crohn's disease, only infliximab can induce clinical remission. As the differential clinical efficacy was likely to be caused by biological effects other than mere neutralization of soluble TNF-□, we here investigated reverse signaling through transmembrane TNF-□mTNF) induced by these drugs. Both infliximab and etanercept induced E-selectin expression on human Jurkat T cells stably transfected with mTNF, however only infliximab was able to induce IL-10 production, apoptosis, ROS accumulation and G1 cell cycle arrest. We next examined the element of the mTNF essential for these biological effects induced by infliximab. Cytoplasmic serine residues at positions 2,5 and 27 of mTNF were sequentially substituted to alanine by site-directed mutagenesis. Infliximab-induced apoptosis and cell cycle arrest were completely abrogated by substitution of all of these three cytoplasmic serine residues. In this study, we revealed that novel biological effects induced by infliximab and etanercept were mediated by reverse signaling of mTNF, which might explain the differential clinical efficacy of these anti-TNF-□ agents. We also clarified that cytoplasmic serine residues were critical for the signal transduction through mTNF.

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [Publications] Sawabe T, Horiuchi T, et al.: "Aberrant HS-1 molecule in a patient with systemic lupus erythematosus"Genes Immun.. 4(2). 122-131 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Koyama T, Tsukamoto H, et al.: "Novel polymorphism of the human APRIL gene is associated with systemic lupus erythematosus"Rheumatology. 42. 980-985 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Harashima S, Tsukamoto H, et al.: "Successful treatment of invasive pulmonary aspergillosis by transbronchial injection of urinary trypsin inhibitor and amphotericin B"Acta Haematol. 109. 156-157 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Harashima S, Tsukamoto H, et al.: "Osteoprotegerin and receptor activator of nuclear factor kBligand expression in fibroblast-like synoviocytes from RA and patients"Rheumatology. 43. 396-397 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mitoma H, Horiuchi T, et al.: "Binding activities of infliximab and etanercept to transmembrane tumor necrosis factor-α"Gastroenterology. 126(3). 934-935 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sawabe T, Horiuchi T, Koga R, Tsukamoto H, Kojima T, Harashima S, Kikuchi Y, Niho Y, Watanabe T.: "Aberrant HS1 molecule in a patient with systemic lupus erythematosus."Genes Immun.. 4(2). 122-131 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Koyama T, Tsukamoto H, Masumoto K, Himeji D, Hayashi K, Harada M, Horiuchi T.: "A novel polymorphism of human APRIL gene is associated with systemic lupus erythematosus."Rheumatology. 42. 980-985 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Harashima S, Tsukamoto H, Otsuka J, Horiuchi T.: "Successful treatment of invasive pulmonary aspergillosis by transbronchial injection of urinary trypsin inhibitor and amphotericin B"Acta Haematol.. 109. 156-157 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Harashima S, Tsukamoto H, Horiuchi T.: "Osteoprotegerin and receptor activator for nuclear factor κB ligand expression in fibroblast-like synoviocytes from rheumatoid arthritis and osteoarthritis patients."Rheumatology. 43. 396-397 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mitoma H, Horiuchi T, Tsukamoto H.: "Binding activities of infliximab and etanercept to transmembrane tumor necrosis factor (TNF)-□."Gastroenterology. 126(3). 934-935 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sawabe T, Horiuchi T, et al.: "Aberrant HS-1 molecule in a patient with systemic lupus erythematosus"Genes Immun.. 4. 123-131 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Koyama T, Tsukamoto H, et al.: "Novel polymorphism of the human APRIL gene is associated with systemic lupus erythematosus"Rheumatology. 42. 980-985 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Harashima S, Tsukamoto H, et al.: "Successful treatment of invasive pulmonary aspergillosis by transbronchial injection of urinary trypsin inhibitor and amphotericin B"Acta Haematol. 109. 156-157 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Harashima S, Tsukamoto H, et al.: "Osteoprotegerin and receptor activator of nuclear factor kBligand expression in fibroblast-like synoviocytes from RA and OA patients"Rheumatology. 43. 396-397 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mitoma H, Horiuchi T, et al.: "Binding activities of infliximab and etanercept to transmembrane tumor necrosis factor-α"Gastroenterology. 126. 934-935 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Himeji D, Horiuchi T, et al.: "Characterization of caspase-8L : a novel isoform of caspase-8 that behaves as an inhibitor of the caspase cascade"Blood. 99(11). 4070-4078 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Horiuchi T, Nishimukai H, et al.: "Molecular bases for human complement C7 polymorphisms, C7^*3 and C7^*4"Biochem Biophys. Res. Commun.. 298. 450-455 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kikuchi Y, Horiuchi T, et al.: "RP105-lacking B cells from lupus patients are responsible for the production of immunoglobulins and autoantibodies"Arthritis Rheum.. 46(12). 3259-3265 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Koyama T, Tsukamoto H, et al.: "A novel polymorphism of the human APRIL gene is associated with systemic lupus erythematosus"Rheumatology. 42. 1-6 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sawabe T, Horiuchi T, et al.: "Aberrant HS1 molecule in a patient with systemic lupus erythematosus"Genes Immun.. (in press). (2003)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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