Rheumatoid arthritis (RA) is characterized by recruitment and activation of immune effector cells in the inflamed synovium. Many cytokines have been detected in RA synovial tissue (ST) and synovial fluid (SF), and an important role for cytokines in the pathogenesis of RA has been suggested by clinical trials and experiments using animal models. However, the complexity of cytokine expression has limited analysis of mechanisms by which cytokines regulate synovitis and has limited the identification of the most important cytokines. Activation of transcriptional responses by numerous inflammatory cytokines is mediated by only six known STAT transcription factors. Analysis of STAT activity offers a unique opportunity to determine how cells actually respond to a complex inflammatory environment, and to characterize the mechanisms by which cytokines drive the inflammatory process. Furthermore, STATs are an attractive target for therapeutic intervention, since blocking an individual STAT can result in a block of a select group of cytokines without concomitant global immunosuppression. The investigators have obtained evidence that Stat3 is constitutively active in RA SF and ST-cells. RA SFs activated Stat3 in monocytes, and IL-6 was the major Stat3-activating factor. Activation of Stat3 was necessary, but not sufficient, for activation of gene expression. Stat3 has been implicated in the regulation of several inflammatory genes, and the investigators hypothesize that Stat3 contributes to the pathogenesis of RA by driving expression of genes that contribute to inflammation and tissue destruction. Given the expression of multiple cytokines in RA, additional STATs likely play an equally important role, especially by regulating T-cell phenotype and contribution to synovitis. Further analysis of the regulation of STATs during synovitis and the role of STATs in driving synovial inflammation will yield insight into the mechanisms of pathogenesis of this disease process. Therefore, the investigators' specific aims are: (1) To characterize STAT activity in synovial cells in RA and an animal model, and identify individual STAT proteins that likely play an important role in pathogenesis. (2) To determine the mechanisms that regulate activity of the Stat3, and the effects of perturbing Stat3 activity on synovitis. (3) To demonstrate that the STAT(s) identified in Aim 1 actually plays a causal role in pathogenesis of synovitis, and investigate the mechanisms of STAT action.
