Cytokines have been implicated in the pathogenesis of several inflammatory diseases, including rheumatoid arthritis (RA). A key role for the inflammatory cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1) in RA pathogenesis has been demonstrated by the efficacy of biological therapies that block TNF and IL-1 activity. Cytokines other than TNFalpha and IL-I are important in RA pathogenesis, and recently there has been increasing interest in the pathogenic role of cytokines that activate the Jak-STAT signaling pathway, including IL-6, IL-15, and IFNgamma. Immunosuppressive and anti-inflammatory cytokines, including TGFbeta, IL-10, and IL-1RA are highly and consistently expressed during RA synovitis. The idea that the balance between levels of pro- and anti-inflammatory factors is important in regulating inflammation in RA has gained broad acceptance among RA researchers. Our work aims to extend this paradigm to take into account that cellular responsiveness to cytokines is regulated in a dynamic fashion, and that signal transduction crosstalk, synergy, and antagonism among pro- and anti-inflammatory synovial factors will regulate the balance of cytokine activity. We have identified two examples of how cytokine signaling can be modulated by the inflammatory RA synovial microenvironment in ways that can contribute to pathogenesis: 1. Signaling by the potent anti-inflammatory cytokine IL-10 is suppressed in RA synovial macrophages, and can be blocked by inflammatory factors. 2. Expression of Stat1, a pro-inflammatory molecule that mediates cytokine signal transduction and transcriptional regulation, is highly elevated in RA synovial cells. Cells expressing elevated Stat1 are hyper-responsive to activation by low concentrations of IFNgamma and exhibit an altered, hyper-inflammatory response to IL-6. In this application, we propose to delineate the mechanisms by which inflammatory pathways operative in RA synovium suppress IL-10 signaling, and to investigate the functional consequences of elevated Stat1 expression on cell phenotype and cytokine activity in the context of RA pathogenesis. Greater understanding of the molecular mechanisms that regulate IL-10 signaling and Stat1 activity will yield insight into cytokine regulation of RA pathogenesis, and will identify novel therapeutic approaches to manipulate cytokine balance in RA at the level of signal transduction.
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