Preferential and persistent activation of the STAT1 pathway in rheumatoid synovial fluid cells

Objective. Inflammatory cytokines such as interleukin 1 (IL-1), IL-6, and t umor necrosis factor-a are produced in great quantities in inflamed rheumat oid joints. However, little is known about the pathogenic significance of e ach cytokine in the proliferative synovitis and destruction of bone and joi nt. We investigated the role of cytokine receptor signals transduced into c ells at the foci of rheumatoid inflammation. Methods. Synovial fluid (SF) cells from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) were examined for the activation of a group of cytokine receptor signaling molecules, signal transducers and activators o f transcription (STAT). Results. DNA binding of STAT1 in SF cells was observed in 8 out of 14 patie nts with RA, but in none of the 10 patients with OA studied, and this was p revented by preincubation of these cells with neutralizing anti-IL-6 antibo dy. IL-6 activated both STAT1 and STAT3 in normal peripheral blood (PB) leu kocytes, and preferentially STAT1 in rheumatoid SF cells. Moreover, STAT1 a ctivation in rheumatoid SF cells appeared to be continuous, in contrast to the transient activation in normal PB leukocytes. Conclusion. STAT1 and STAT3 are differentially regulated in response to IL- 6 in different cell types. The continuous STAT1 activation may be of pathog enic significance in the progression and persistence of RA.