Certain pro-inflammatory cytokines, especially IL-1 and TNFalpha, are expressed in the majority of patients with RA and play an important role in pathogenesis. Important targets for pro-inflammatory cytokines are synovial fibroblasts, which proliferate, assume an invasive morphology, and invade and degrade cartilage. One striking characteristic of RA synovitis is the consistently high expression of immunosuppressive and anti-inflammatory cytokines, such as IL10 and TGF-beta, and of members of the IL-6 family of cytokines. Although IL-6-related cytokines have often been considered pro-inflammatory, more recent results suggest that they (and the downstream transcription factor Stat3) have anti-inflammatory actions on synovial fibroblasts and possibly macrophages. One major school of thought holds that the balance between pro- and anti-inflammatory factors determines the progression of disease, and that defects in the de-activation phase of inflammation play a critical role in the pathogenesis of RA. One important issue is why abundant expression of anti-inflammatory cytokines does not lead to resolution of inflammation in RA? We have explored the possibility that the anti-inflammatory actions of IL-10 and IL-6-related cytokines may be blocked in RA synovium at the level of signal transduction. We have found that IL-1, TNFalpha, and H2O2 suppress IL-6 and IL-10 activation of Stat3 DNA-binding and tyrosine phosphorylation by a mechanism that appears dependent on mitogen-activated protein kinases (MAPKs). Inhibition of Stat3 correlated with inhibition of expression of IL-6-inducible genes that have an anti-inflammatory function. We hypothesize that inhibition of IL-6 and IL-10 signaling and Stat3 activity by inflammatory factors that are present during synovitis contributes to pathogenesis by blocking de-activation of synovial inflammation. We propose to delineate the mechanisms underlying crosstalk between inflammatory/MAPK and IL-6/IL-10 Jak-STAT signaling pathways in synovial fibroblasts, and to investigate the functional consequences of this crosstalk in the context of RA pathogenesis. Greater understanding of mechanisms that block anti-inflammatory cytokine action will be helpful in designing novel therapeutic approaches to shift the balance of cytokine activity to limit inflammation and progression of disease.
Our specific aims are to: (1) Identify the molecular mechanism by which the inflammatory cytokines IL-1 and TNFalpha, and ROIs, inhibit activation of Stat3 by IL-6-related cytokines and IL-10 in RA synovial fibroblasts. (2) Determine which MAPKs play an important role in inhibition of IL-6 and IL-10 signaling in RA synovial fibroblasts. (3) Characterize the functional consequences of modulation of IL-6 and IL-10 signal transduction by inflammatory factors on synovial fibroblast phenotype.
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