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. 2004 Jun;50(6):2014-23.
doi: 10.1002/art.20302.

Local activation of STAT-1 and STAT-3 in the inflamed synovium during zymosan-induced arthritis: exacerbation of joint inflammation in STAT-1 gene-knockout mice

Alfons S K de Hooge  1 , Fons A J van de Loo, Marije I Koenders, Miranda B Bennink, Onno J Arntz, Thomas Kolbe, Wim B van den Berg
Affiliations

Local activation of STAT-1 and STAT-3 in the inflamed synovium during zymosan-induced arthritis: exacerbation of joint inflammation in STAT-1 gene-knockout mice

Alfons S K de Hooge et al. Arthritis Rheum. 2004 Jun.

Abstract

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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