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CP690,550 inhibits oncostatin M-induced JAK/STAT signaling pathway in rheumatoid synoviocytes

Kiyoshi Migita1, Atsumasa Komori, Takafumi Torigoshi

  • 1Department of Rheumatology and Clinical Research Center, Nagasaki Medical Center, Kubara 2-1001-1, Omura 856-8652, Japan. migita@nmc.hosp.go.jp

Arthritis Research & Therapy
|May 10, 2011
PubMed
Abstract

Insights

A JAK inhibitor, CP690,550, effectively reduced interleukin-6 production and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway activation in rheumatoid arthritis synoviocytes. This suggests potential for treating rheumatoid synovitis.

Area of Science:

  • Immunology
  • Molecular Biology
  • Pharmacology

Background:

  • Interleukin-6 (IL)-type cytokines signal via the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway.
  • JAK/STAT signaling is implicated in rheumatoid arthritis (RA) pathogenesis, with JAK inhibitors showing promise in clinical trials.
  • This study explores the effects of a JAK inhibitor, CP690,550, on JAK/STAT pathways in rheumatoid synovitis.

Purpose of the Study:

  • To investigate the molecular effects of CP690,550 on JAK/STAT signaling.
  • To examine the role of JAK kinases in rheumatoid synovitis.
  • To assess the potential of CP690,550 in inhibiting pro-inflammatory pathways in RA.

Main Methods:

  • Fibroblast-like synoviocytes (FLS) from RA patients were stimulated with oncostatin M (OSM).
  • Cytokine production (IL-6) was measured using protein chips, real-time PCR, and ELISA.
  • Protein phosphorylation, including STAT and mitogen-activated kinases (MAPKs), was analyzed by Western blot.

Main Results:

  • Oncostatin M (OSM) potently induced IL-6 production in FLS.
  • OSM stimulation activated the JAK/STAT pathway, evidenced by STAT phosphorylation.
  • CP690,550 pretreatment inhibited OSM-induced IL-6 production and blocked JAK/STAT and MAPK activation.

Conclusions:

  • IL-6-type cytokines contribute to rheumatoid synovitis via JAK/STAT pathway activation in synoviocytes.
  • Inhibiting these inflammatory pathways with CP690,550 may be a viable therapeutic strategy for RA.
  • CP690,550 demonstrates potential for treating rheumatoid arthritis by targeting key signaling cascades.

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