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2004 Fiscal Year Final Research Report Summary

The roles of pro-inflammatory cytokines on induction of acute phase proteins in inflammatory diseases

Research Project

Project/Area Number 15390314
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field 膠原病・アレルギー・感染症内科学
Research InstitutionOsaka University

Principal Investigator

YOSHIZAKI Kazuyuki  Osaka University, School of Health and Sport Sciences, Professor, 健康体育部, 教授 (90144485)

Project Period (FY) 2003 – 2004
KeywordsSerum amyloid A(SAA) / Interleukin 6(IL-6) / Anti-IL-6R antibody / STAT3 / C / EBPβ / NF-κB / Chronic inflammatory disease / AA amyloidosis
Research Abstract

According to the report by Betts et al. on induction of human SAA2 gene, the transcription factors of C/EBPβ and NF-κB are involved in the synergistic activation by IL-6 and IL-1. We established a SAA isoform real-time quantitative RT-PCR assay to estimate the mRNA expression of each of the SAA isoforms after cytokine stimulation. We demonstrate that IL-6 were necessary for the synergistic induction of SAA genes among IL-6,Il-1β and TNF-α and that IL-6 blockade (anti-IL-6R antibody) but not TNF-α or Il-1 blockade completely inhibits the synergistic induction of SAA1 and SAA2 genes in the triple stimulation. Our results indicate that IL-6 plays a critical role in the synergistic activation of human SAA gene by IL-6,IL-1 and TNF-α. Furthermore, we suggest that JAK/STAT3 pathway plays an important role than C/EBPβ through MAP kinase pathway.
Next we provide evidence STAT3 plays an essential role in the cytokine-driven of SAA expression, although the human SAA gene has no typical STAT3 response element(RE) in its promoters. STAT3 and NF-κB p65 first form a complex following IL-1 and IL-6(IL-1+6) stimulation, and STAT3 then interacts with no-consensus sequences at a 3'-site of the NF-κB RE of the SAA gene promoter. Moreover, co-expression of p300 with STAT3 dramatically enhanced the transcriptional activity of SAA. The formation of a complex with STAT3,NF-κB p65, and p300 is essential for the synergistic induction of the SAA gene by IL-1+6 stimulation. Our findings are expected to aid the understanding of the inflammatory status.

  • Research Products

    (15 results)

All 2005 2004 2003

All Journal Article (14 results) Book (1 results)

  • [Journal Article] Therapeutic efficacy of humanized recombinant anti-IL 6-receptor antibody for children with systemic-onset juvenile idiopathic arthritis.2005

    • Author(s)
      Yokota S, et al.
    • Journal Title

      Arthritis Rheum. 52

      Pages: 818-825

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Therapeutic efficacy of humanized recombinant anti-IL 6-receptor antibody for children with systemic-onset juvenile idiopathic arthritis.2005

    • Author(s)
      Yokota S, Miyamae T, Imagawa T, Iwata N, Katakura S, Mori M, Woo P, Nishimoto N, Yoshizaki K, Kishimoto T.
    • Journal Title

      Arthritis Rheum. 52

      Pages: 818-825

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] IL-6 plays a critical role in the synergistic induction of human serum amyloid A (SAA) gene when stimulated with proinflammatory cytokines as analyzed with an SAA isoform real-time quantitative RT-PCR assay system.2004

    • Author(s)
      Hagihara K, et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 314

      Pages: 363-369

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Anti-interleukin-6 receptor antibody inhibits murine AA-amyloidosis.2004

    • Author(s)
      Mihara M, et al.
    • Journal Title

      J.Rheum. 31

      Pages: 1132-1138

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody : a multicenter, double-blind, placebo-controlled trial.2004

    • Author(s)
      Nishimoto N, et al.
    • Journal Title

      Arthritis Rheum. 50

      Pages: 1761-1769

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease.2004

    • Author(s)
      Ito A, et al.
    • Journal Title

      Gastroenterology 126

      Pages: 989-996

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Blockade of interleukin-6 receptor suppresses reactive astrogliosis and ameliorates functional recovery in experimental spinal cord injury.2004

    • Author(s)
      Okada S, et al.
    • Journal Title

      J.Neurosci.Res. 76

      Pages: 265-276

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] IL-6 plays a critical role in the synergistic induction of human serum amyloid A (SAA) gene when stimulated with proinflammatory cytokines as analyzed with an SAA isoform real-time quantitative RT-PCR assay system.2004

    • Author(s)
      Hagihara K, Nishikawa T, Isobe T, Song J, Sugamata Y, Yoshizaki K.
    • Journal Title

      Biochem.Biophys.Res.Commun. 314

      Pages: 363-369

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Blockade of interleukin-6 receptor suppresses reactive astrogliosis and ameliorates functional recovery in experimental spinal cord injury.2004

    • Author(s)
      Okada S, Nakamaura M, Mikami Y, Shimazaki T, Mihara M, Ohsugi Y, Iwamoto Y, Yoshizaki K, Kishimoto T, Okano H.
    • Journal Title

      J.Neurosci.Res. 76

      Pages: 265-276

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease.2004

    • Author(s)
      Ito A, Takazoe M, Fukuda Y, Hibi T, Kusugami K, Andoh A, Matsumoto T, Yamamura T, Azuma J, Nishimoto N, Yoshizaki K, Shimoyama T, Kishimoto T.
    • Journal Title

      Gastroenterology 126

      Pages: 989-996

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody : a multicenter, double-blind placebo-controlled trial.2004

    • Author(s)
      Nishimoto N, Yoshizaki K, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Hashimoto J, Azuma J, Kishimoto T.
    • Journal Title

      Arthritis Rheum. 50

      Pages: 1761-1769

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Anti-interleukin-6 receptor antibody inhibits murine AA-amyloidosis.2004

    • Author(s)
      Mihara M, Shiina M, Nishimoto N, Yoshizaki K, Kishimoto T, Akamatsu K.
    • Journal Title

      J.Rheum. 31

      Pages: 1132-1138

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Anti-interleukin-6 receptor antibody therapy reduces vascular endotherlial growth factor(VEGF) production in rheumatoid arthritis.2003

    • Author(s)
      Nakahara H, Song J, Sugimoto M, Hagihara K, Kishimoto T, Yoshizaki K, Nishimoto N.
    • Journal Title

      Arthritis Rheum. 48

      Pages: 1521-1529

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Toxicity, pharmacokinetics, and dose finding study of repetitive treatment with humanized anti-interleukin 6 receptor antibody MRA in rheumatoid arthritis : phase I/II clinical study.2003

    • Author(s)
      Nishimoto N, Yoshizaki K, Maeda, K, Kuritani T, Deguchi H, Sato B, Imai N, Kakehi T, Takagi N, Suemura M, Kishimoto T.
    • Journal Title

      J.Rheum. 30

      Pages: 1426-1435

    • Description
      「研究成果報告書概要(欧文)」より
  • [Book] サイトカイン・ケモカインのすべて 第三版改訂新版(笠倉新平、松島綱治編)2004

    • Author(s)
      吉崎和幸 他
    • Total Pages
      25
    • Publisher
      日本医学館
    • Description
      「研究成果報告書概要(和文)」より

URL: 

Published: 2006-07-11  

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