STAT proteins play an important role in cytokine signaling. Some investigators have reported preferential activation of STAT‐1, and others have reported preferential activation of STAT‐3, in response to endogenous interleukin‐6 (IL‐6), in patients with rheumatoid arthritis. The present study was undertaken to investigate synovial STAT‐1 and STAT‐3 activation in an experimental animal model of arthritis.

Zymosan was injected intraarticularly into naive wild‐type (WT), IL‐6^−/−, and STAT‐1^−/− mice to induce arthritis. Western blots of synovial lysates were probed with phosphospecific antibodies to detect STAT‐1/STAT‐3 activation. Inflammation was assessed histologically. Synovial gene expression of the STAT‐induced feedback inhibitors suppressor of cytokine signaling 1 (SOCS‐1) and SOCS‐3 in WT and STAT‐1^−/− mice was investigated by reverse transcriptase–polymerase chain reaction.

STAT‐3 was activated in inflamed synovium of WT mice throughout the course of disease, whereas activated STAT‐1 was observed only during the chronic phase. In IL‐6^−/− mice, STAT activation was limited to STAT‐3 on day 1. Although macrophage influx was not inhibited, disease went into remission after day 7 in IL‐6^−/− mice. STAT‐1 deficiency resulted in exacerbation of chronic joint inflammation and granuloma formation. In STAT‐1^−/− mice, STAT‐3 activation in the inflamed joints was unaltered as compared with WT mice. However, synovial SOCS‐1, but not SOCS‐3, gene expression was markedly reduced in STAT‐1^−/− mice.

The results in the IL‐6^−/− mice suggest that STAT‐3 is involved in the chronicity of ZIA. Exacerbation of arthritis in STAT‐1^−/− mice suggests an opposing effect of STAT‐1, i.e., suppression of joint inflammation. The expression of SOCS‐1 could be the underlying mechanism by which STAT‐1 controls joint inflammation.