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

Fibroblast-like synoviocytes (FLS) were isolated from RA patients and stimulated with recombinant oncostatin M (OSM). The cellular supernatants were analyzed using cytokine protein chips. IL-6 mRNA and protein expression were analyzed by real-time PCR method and ELISA, respectively. Protein phosphorylation of rheumatoid synoviocytes was assessed by Western blot using phospho-specific antibodies.OSM was found to be a potent inducer of IL-6 in FLS. OSM stimulation elicited rapid phosphorylation of STATs suggesting activation of the JAK/STAT pathway in FLS. CP690,550 pretreatment completely abrogated the OSM-induced production of IL-6, as well as OSM-induced JAK/STAT, and activation of mitogen-activated kinases (MAPKs) in FLS.These findings suggest that IL-6-type cytokines contribute to rheumatoid synovitis through activation of the JAK/STAT pathway in rheumatoid synoviocytes. Inhibition of these pro-inflammatory signaling pathways by CP690,550 could be important in the treatment of RA.Rheumatoid arthritis (RA) is a chronic inflammatory disease that is characterized by the activation and proliferation of synovial tissues with associated degradation of articular cartilage [1]. Synovial fibroblasts are believed to play an important role in rheumatoid synovitis through the production of a variety of inflammatory mediators [2]. Activation of synovial fibroblasts is mediated in large part by cytokines, such as IL-1 or TNF-α, which are produced by monocytes/macrophages [3]. However, other cytokines likely participate in the process of synovial cell activation. Of the IL-6-related cytokines, oncostatin M (OSM) is another product of macrophages and activated T cells that is elevated in the synovial fluids of RA patients [4,5]. Moreover, OSM stimulates chemokine and matrix metalloproteimase (MMPs) production suggesting its important effects in synovial inflammation [6]. IL-6-type cytokines exert their effects via the signal transducer gp130 leading to the activation of the Janu