Inhibition of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway in rheumatoid synovial fibroblasts using small molecule compounds.

• Project/Area Number: 23591452
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Department of Clinical Research, National Hospital Organization Nagasaki Medical Center
• Principal Investigator: MIGITA Kiyoshi 独立行政法人国立病院機構(長崎医療センター臨床研究センター), その他部局等, その他 (60264214)
• Project Period (FY): 2011-04-28 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 関節リウマチ / 滑膜細胞 / シグナル伝達 / ヤヌスキナーゼ / JAKs / STATs / サイトカインレセプター / 炎症性サイトカイン / JAKキナーゼ / STAT / JAK阻害剤 / T細胞 / CP690, 550

Outline of Final Research Achievements

We investigated if JAK-3-selective inhibition alone could disrupt cytokine signalling in rheumatoid synovial fibroblasts. In-vitro studies were performed using synovial fibroblasts isolated from patients with RA. The JAK inhibitors CP-690,550 and INCB028050 both suppressed activation of JAK-1/-2/-3 and downstream STAT-1/-3/-5, as well as the expression levels of target proinflammatory genes (MCP-I, SAA1/2) in oncostatin-M (OSM)-stimulated rheumatoid synovial fibroblasts. In contrast, the JAK-3-selective inhibitor, PF-956980, suppressed STAT-1/-5 activation but did not affect STAT-3 activation in OSM-stimulated rheumatoid synovial fibroblasts. These data suggest that JAK-3-selective inhibition alone is insufficient to control STAT-3-dependent signalling in rheumatoid synovial fibroblasts, and inhibition of JAKs, including JAK-1/-2, is needed to control the proinflammatory cascade in RA.

Research Products

• [Journal Article] Migita K, Izumi Y, Jiuchi Y, Kozuru H, Kawahara C, Izumi M, Sakai T, Nakamura M, Motokawa S, Nakamura T, Kawakami A.Effects of Janus kinase inhibitor tofacitinib on circulating serum amyloid A and interleukin-6 during treatment for rheumatoid arthritis. (2014)
  • Author(s): Migita K, Izumi Y, Jiuchi Y, Kozuru H, Kawahara C, Izumi M, Sakai T, Nakamura M, Motokawa S, Nakamura T, Kawakami A.
  • Journal Title: Clinical and experimental immunology Volume: 175 Pages: 208-14
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Effects of Janus kinase inhibitor tofacitinib on circulating serum amyloid A and interleukin-6 during treatment for rheumatoid arthritis. (2014)
  • Author(s): Migita K1, Izumi Y, Jiuchi Y, Kozuru H, Kawahara C, Izumi M, Sakai T, Nakamura M, Motokawa S, Nakamura T, Kawakami A.
  • Journal Title: Clin Exp Immunol. Volume: 175 Issue: 2 Pages: 208-214
  • DOI: 10.1111/cei.12234
  • Peer Reviewed
• [Journal Article] Inhibition of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway in rheumatoid synovial fibroblasts using small molecule compounds. (2013)
  • Author(s): Migita K, Izumi Y, Torigoshi T, Satomura K, Izumi M, Nishino Y, Jiuchi Y, Nakamura M, Kozuru H, Nonaka F, Eguchi K, Kawakami A, Motokawa S.
  • Journal Title: Clin Exp Immunol. Volume: 174 Issue: 3 Pages: 356-363
  • DOI: 10.1111/cei.12190
  • Peer Reviewed
• [Journal Article] JAK3阻害薬． (2013)
  • Author(s): 右田清志，和泉泰衛．
  • Journal Title: 炎症と免疫 Volume: 21 Pages: 37-44
  • Peer Reviewed
• [Journal Article] CP690,550 inhibits oncostatin M-induced JAK/STAT signaling pathway in rheumatoid synoviocytes. (2011)
  • Author(s): Migita K, Komori A, Torigoshi T, Maeda Y, Izumi Y, Jiuchi Y, Miyashita T, Nakamura M, Motokawa S, Ishibashi H.
  • Journal Title: Arthritis Res Ther. Volume: 13 Issue: 3
  • DOI: 10.1186/ar3333
  • Peer Reviewed
• [Journal Article] Inhibitory effects of the JAK inhibitor CP690,550 on human CD4(+) T lymphocyte cytokine production. (2011)
  • Author(s): Migita K, Miyashita T, Izumi Y, Koga T, Komori A, Maeda Y, Jiuchi Y, Aiba Y, Yamasaki S, Kawakami A, Nakamura M, Ishibashi H.
  • Journal Title: BMC Immunol. Volume: 12 Issue: 1 Pages: 51-51
  • DOI: 10.1186/1471-2172-12-51
  • Peer Reviewed