Cross-talk between IL-1 and IL-6 signaling pathways in rheumatoid arthritis synovial fibroblasts

The balance between pro- and anti-inflammatory cytokines plays an important role in determining the severity of inflammation in rheumatoid arthritis ( RA). Antagonism between opposing cytokines at the level of signal transduct ion plays an important role in many other systems. We have begun to explore the possible contribution of signal transduction cross-talk to cytokine ba lance in RA by examining the effects of IL-1, a proinflammatory cytokine, o n the signaling and action of IL-6, a pleiotropic cytokine that has both pr o- and anti-inflammatory actions, In RA synovial fibroblasts. Pretreatment with IL-1 suppressed Janus kinase-STAT signaling by IL-6, modified patterns of gene activation, and blocked IL-6 induction of tissue inhibitor of meta lloproteases 1 expression. These results suggest that proinflammatory cytok ines may contribute to pathogenesis by modulating or blocking signal transd uction by pleiotropic or anti-inflammatory cytokines. The mechanism of inhi bition did not require de novo gene activation and did not depend upon tyro sine phosphatase activity, but, instead, was dependent on the p38 stress ki nase. These results identify a molecular basis for IL-1 and IL-6 cross-talk in RA synoviocytes and suggest that, in addition to levels of cytokine exp ression, modulation of signal transduction also plays a role in regulating cytokine balance in RA.