Rheumatoid arthritis (RA) is a chronic inflammatory process that is characterized by the presence of activated monocytes/macrophages, T cells, B cells, plasma cells, and synovial fibroblasts in inflamed joints. Cytokines have been implicated in the activation of these cells and the pathogenesis of disease. Recent observations in a number of animal models of RA and in RA patients suggest that interleukin-6 (IL-6) plays a critical role in the pathogenesis have not been clarified, but potential mechanisms include activation of macrophages, stimulation of local antibody (rheumatoid factor) production, activation of T cells, and stimulation of myeloid and fibroblast differentiation into cells which directly degrade bone and cartilage. The activity of many cytokines, including IL-6, is mediated, in large part, by a major signal transduction pathway that utilizes Janus protein tyrosine kinases (Jaks) and STAT transcription factors. We have found that Stat3 is constitutively active in RA synovial fluid and tissues cells, that synovial fluids activate Stat3 in control cells, and that the major synovial fluid activator of Stat3 is IL-6. These observations have prompted an investigation of molecular mechanisms of inhibition of IL-6 signaling and Stat3 activation. One rapidly acting investigation of molecular mechanisms of inhibition of IL-6 signaling and Stat3 activation. One rapidly acting inhibitory pathway that we have described involves the kinase cascade that activates the extracellular stimulus-regulated kinase (ERK) subfamily of mitogen activated protein kinases (hereafter termed the MEK-ERK pathway). This pathway inhibits signaling upstream of Stat3 activation and is relative specific for IL-6 and related cytokines that share the gp130 signaling subunit. We hypothesize that inhibition of IL-6 signaling is mediated by ERK kinase-dependent phosphorylation of the IL-6 receptor or an associated signaling molecule. We propose to delineate the molecular mechanism of inhibition and identify important regulatory molecules that can be targeted by novel therapies aimed at inhibiting cell activation during RA. Therefore, our specific aims are: (1) identify the IL-6 receptor sequences that mediate inhibition of signaling by the MEK-ERK pathway. (2) Determine the mechanism by which ERK-mediated post-translational modification of the IL-6 receptor or associated signaling molecules regulates the function of this receptor. (3) Characterize the functional consequences of ERK-mediated inhibition of IL-6 signal transduction using the M1 myeloid cell differentiation system.
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