SMAD-STAT signaling network in the pathogenesis of rheumatoid arthritis

• Project/Area Number: 16K09908
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Tokyo Medical University
• Principal Investigator: Mamura Mizuko 東京医科大学, 医学部, 兼任教授 (60400686)
• Co-Investigator(Kenkyū-buntansha): 住田 孝之 筑波大学, 医学医療系, 教授 (00183054) ; 尹 晶煥 東京医科大学, 医学部, 兼任助教 (30748885)
• Research Collaborator: KATO Mitsuyasu ; SUDO Katsuko ; MIYAZAWA Keiji ; KURODA Masahiko
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 関節リウマチ / Th17 / TGF-β / Smad / IL-6 / Stat / Smad3/4 / STAT3 / Th17細胞 / TGF-beta / SMAD / STAT / 免疫学 / シグナル伝達 / 細胞・組織

Outline of Final Research Achievements

It has been reported that TGF-β in cooperation with IL-6 induces Th17 differentiation. However, we have found that canonical TGF-β signaling pathway via Smad3 and Smad4 rather suppresses Th17 differentiation by inducing the negative regulators of the crucial signaling molecule of IL-6, STAT3 such as SOCS3, SHP1 and SHP2 using in vitro culture and a murine collagen-induced arthritis model. We have further discovered that the expression patterns of these molecules in peripheral blood mononuclear cells (PBMCs) from rheumatoid arthritis patients significantly correlate with the efficacy of the biologics targeting TNF-α or IL-6.

Academic Significance and Societal Importance of the Research Achievements

炎症性サイトカインを標的にした生物学的製剤は関節リウマチの治療成績を飛躍的に改善しましたが、ある製剤が無効で他の製剤に切り替えなければならない場合も少なからずあります。生物学的製剤は高価である為、患者様別にどのサイトカインを標的にした製剤が有効であるか治療前に判定することが望まれますが、現時点で明確に予測できる方法はありませんでした。本研究は、関節リウマチの病態に重要な炎症性細胞の分化のコントロールについて新しいメカニズムを明らかにし、生物学的製剤の治療効果を予測し得るマーカーを発見しました。

Research Products

• [Presentation] Canonical TGF-β signaling via SMAD3 and SMAD4 suppresses STAT3-induced arthritogenic Th17 differentiation (2018)
  • Author(s): Jeong-Hwan Yoon, Eunjin Bae, Ji Hyeon Ju, Masahiro Yokosawa, Yuya Kondo, Isao Matsumoto, Takayuki Sumida, Mizuko Mamura
  • Organizer: 第5回 日本リウマチ学会ベーシックリサーチカンファレンス
• [Presentation] Canonical TGF-β signaling via Smad3/4 suppresses Th17 differentiation (2018)
  • Author(s): Jeong-Hwan Yoon, Eunjin Bae, Ji Hyeon Ju, In-Kyu Lee, Isao Matsumoto, Takayuki Sumida, Mizuko Mamura
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Canonical TGF-β signaling via C-terminally phosphorylated Smad3 and Smad4 suppresses Th17 differentiation (2018)
  • Author(s): 真村瑞子
  • Organizer: 第62回日本リウマチ学会総会・学術集会International Concurrent Workshop3: Immunology
  • Int'l Joint Research
• [Presentation] 関節炎でのTh17分化 (2017)
  • Author(s): 真村瑞子
  • Organizer: 第38回日本炎症・再生医学会シンポジウム13骨・軟骨の炎症と再生（骨免疫学会合同）
  • Invited
• [Presentation] Canonical SMADシグナルとnon-canonical SMADシグナルによる免疫細胞分化制御 (2017)
  • Author(s): 真村瑞子
  • Organizer: 2017年度生命科学系学会合同年次大会（ConBio2017）ワークショップ: Smadシグナルのcanonical経路とnon-canonical経路
  • Invited
• [Presentation] Canonical TGF-β signaling via Smad3/4 regulates expression and function of SOCS3 to suppress Th17 differentiation (2016)
  • Author(s): Mizuko Mamura, Jeong-Hwan Yoon, Ji Hyeon Ju, Isao Matsumoto, Takayuki Sumida
  • Organizer: The 60th Annual General Assembly and Scientific Meeting of the Japan College of Rheumatology
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2016-04-23
  • Int'l Joint Research