Local activation of STAT-1 and STAT-3 in the inflamed synovium during zymosan-induced arthritis

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Arthritis Rheum. 2004 Jun;50(6):2014-23.

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.

de Hooge AS, van de Loo FA, Koenders MI, Bennink MB, Arntz OJ, Kolbe T,

van den Berg WB.

University Medical Center Nijmegen, Nijmegen, The Netherlands.

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.

PMID: 15188379

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