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The elucidation and clinical application of the hepcidin-ferroportin regulation mechanism in inflammatory anemia

Research Project

Project/Area Number 25461452
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Hematology
Research InstitutionOsaka University

Principal Investigator

Nakazawa Soken  大阪大学, 産業科学研究所, 招へい准教授 (00535958)

Co-Investigator(Renkei-kenkyūsha) Yoshizaki Kazuyuki  大阪大学, 産業科学研究所, 特任教授 (90144485)
Tomosugi Naohisa  金沢医科大学, 医学部, 教授 (80155580)
Kawabata Hiroshi  京都大学, 医学部, 講師 (10329401)
Uno Kazuko  (財)ルイ・パストゥール医学研究センター, 研究室室長 (50211082)
TANIGAWA Miki  大阪大学, 産業科学研究所, 研究員
Ito Hiroki  大阪大学, 産業科学研究所, 招へい研究員 (60590635)
Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2015: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords炎症性貧血 / ヘプシジン / IL-6 / 関節リウマチ / フェロポルチン / TNF-a / リウマチ / TNFa / tocilizumab / BMP / TNFα / トシリズマブ
Outline of Final Research Achievements

The role of hepcidin and its regulation by multiple inflammatory cytokines in patients with anemia of inflammation (AI) is still largely unknown. In this study, by using anti-cytokine biologics as a tool, we investigated the mechanism of AI in patients with rheumatoid arthritis (RA). We found that tocilizumab (an anti-IL-6 receptor antibody) can reduce serum hepcidin and improve anemia in RA patients, but TNF-a inhibitors (TNFi) displayed significantly weaker effects than tocilizumab on suppressing serum hepcidin levels and increase hemoglobin (Hb) levels. And serum hepcidin reduction by TNFi was accompanied by a decrease in serum IL-6 suggesting that TNFi on reduction of hepcidin was indirect. Our findings indicated that IL-6-induced hepcidin mediated iron metabolism contribute to the pathogenesis of RA-related anemia directly. We also identified the novel regulation mechanisms involving IL-6-mediated induction and TNF-a-mediated inhibition of hepcidin production.

Report

(4 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Research-status Report
  • 2013 Research-status Report
  • Research Products

    (15 results)

All 2015 2014 2013

All Journal Article (5 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 5 results,  Open Access: 2 results,  Acknowledgement Compliant: 1 results) Presentation (10 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results)

  • [Journal Article] Pretreatment Prediction of Individual Rheumatoid Arthritis Patients' Response to Anti-Cytokine Therapy Using Serum Cytokine/Chemokine/ Soluble Receptor Biomarkers.2015

    • Author(s)
      Uno K, Yoshizaki K, Iwahashi M, Yamana J, Yamana S, Tanigawa M, Yagi K.
    • Journal Title

      PLoS One

      Volume: Jul 15;10(7) Issue: 7 Pages: 1-15

    • DOI

      10.1371/journal.pone.0132055

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Tocilizumab for treating rheumatoid arthritis: an evaluation of pharmacokinetics/pharmacodynamics and clinical efficacy2015

    • Author(s)
      Soken-Nakazawa J Song and Kazuyuki Yoshizaki
    • Journal Title

      Expert Opin Drug Metab Toxicol.

      Volume: 11(2) Issue: 2 Pages: 307-316

    • DOI

      10.1517/17425255.2015.992779

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Comparative evaluation of the effects of treatment with tocilizumab and TNF-α inhibitors on serum hepcidin, anemia response and disease activity in rheumatoid arthritis patients2013

    • Author(s)
      Soken-Nakazawa J Song, Mitsuhiro Iwahashi, Naohisa Tomosugi, Kazuko Uno, Jiro Yamana, Seizou Yamana,Tomoyasu Isobe, Hiroki Ito, Hiroshi Kawabata, Kazuyuki Yoshizaki
    • Journal Title

      Arthritis Research & Therapy

      Volume: 15 Issue: 5 Pages: 1-10

    • DOI

      10.1186/ar4323

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Activation-induced cytidine deaminase auto-activates and triggers aberrant gene expression.2013

    • Author(s)
      Tomoyasu Isobe, Soken-Nakazawa J. Song, Prabha Tiwari, et al.
    • Journal Title

      FEBS Lett.

      Volume: 587 Pages: 2487-2492

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Prediction and experimental validation of a putative non-consensus binding site for transcription factor STAT3 in serum amyloid A gene promoter.2013

    • Author(s)
      Prabha Tiwari, Lokesh P. Tripathi, Teppei Nishikawa, Shandar Ahmadb, Soken-Nakazawa J. Song, et al.
    • Journal Title

      Biochim Biophys Acta

      Volume: 1830 Pages: 3650-3655

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Presentation] Opposite role of Soluble Forms of IL-6 Receptor, SIL-6R and sgp130, on the Regulation of Inflammatory Status in Rheumatoid Arthritis2015

    • Author(s)
      Yoshizaki K, Soken-Nakazawa J Song and Uno K
    • Organizer
      12th World Congress on Inflammation
    • Place of Presentation
      Boston, USA
    • Year and Date
      2015-08-08
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Two Soluble Forms of IL-6 Receptor, sIL-6R and sgp130, Regulate Physiological Status and Affect Inflammatory Status Pathologically.2015

    • Author(s)
      Kazuyuki Yoshizaki, Soken Nakazawa and Kazuko Uno.
    • Organizer
      FOCIS2015
    • Place of Presentation
      San Diego, California, USA
    • Year and Date
      2015-06-24
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Suppressing Hepcidin by Tocilizumab Effectively Improve Anemia in Inflammatory Diseases: Clinical Evidence and Basic Mechanisms2014

    • Author(s)
      Kazuyuki Yoshizaki、Soken-Nakazawa J. Song and Hiroshi Kawabata
    • Organizer
      The 56th American Society of Hematology (ASH)
    • Place of Presentation
      San Francisco, CA, USA
    • Year and Date
      2014-12-06 – 2014-12-09
    • Related Report
      2014 Research-status Report
  • [Presentation] .AAアミロイドーシスにおけるIL-6による血清アミロイドAA(SAA)産生メカニズムとそのIL-6標的治療2014

    • Author(s)
      吉崎和幸, PLABHA Tiwari1,中澤宗健, 松村哲平, 荻原圭祐, 伊東大貴
    • Organizer
      第42回日本臨床免疫学会
    • Place of Presentation
      東京
    • Year and Date
      2014-09-25 – 2014-09-27
    • Related Report
      2014 Research-status Report
  • [Presentation] サイトカインによる急性期タンパク(SAA、CRP、Hepcidin)発現機序2014

    • Author(s)
      吉崎和幸,中澤宗健
    • Organizer
      第79回日本インターフェロン・サイトカイン学会
    • Place of Presentation
      札幌
    • Year and Date
      2014-06-19 – 2014-06-20
    • Related Report
      2014 Research-status Report
  • [Presentation] Tocilizumab is More Effective than Tumor Necrosis Factor-a Inhibitors for Improving Anemia in Rheumatoid Arthritis by Inhibiting Hepcidin Production2014

    • Author(s)
      Soken-Nakazawa J. Song and Kazuyuki Yoshizaki
    • Organizer
      MidTerm Conference of ICIS, Interleukin 6 Biology-Pathophysiology-Therapy.
    • Place of Presentation
      Kiel, Germany.
    • Year and Date
      2014-05-14 – 2014-05-17
    • Related Report
      2014 Research-status Report
    • Invited
  • [Presentation] Mechanism of IL-6 induced SAA production and amyloid A deposition in AA Amyloidosis patients with RA2014

    • Author(s)
      Kazuyuki Yoshizaki and Soken-Nakazawa J Song
    • Organizer
      XIVth International Symposium on Amyloidosis
    • Place of Presentation
      Indianapolis, Indiana, USA.
    • Year and Date
      2014-04-27 – 2014-05-01
    • Related Report
      2014 Research-status Report
  • [Presentation] Analysis of the Molecular Mechanisms Leading to Significantly Higher Serum Hepcidin and More Severe Anemia in Multicentric Castleman’s Disease (MCD) Patients Than in Rheumatoid Arthritis (RA) Patients.2013

    • Author(s)
      Soken-Nakazawa J. Song, H Kawabata and K Yoshizaki.
    • Organizer
      The American Society of Hematology(ASH)
    • Place of Presentation
      New Orleans, USA
    • Related Report
      2013 Research-status Report
  • [Presentation] Different mechanism of anemia in chronic inflammatory disease and improvement of anemia by IL-6 blocking therapy.2013

    • Author(s)
      Kazuyuki Yoshizaki and Soken-Nakazawa J Song
    • Organizer
      The Federation of Clinical Immunology Societies (FOCIS)
    • Place of Presentation
      Boston. USA
    • Related Report
      2013 Research-status Report
  • [Presentation] ヘプシジンを介する炎症性貧血のサイトカイン制御機構2013

    • Author(s)
      吉崎和幸、中沢宗健
    • Organizer
      第34回日本炎症再生学会
    • Place of Presentation
      京都(国際会館)
    • Related Report
      2013 Research-status Report

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Published: 2014-07-25   Modified: 2019-07-29  

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