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

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 STATinduced feedback inhibitors suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 in WT and STAT-1 ؊/؊ mice was investigated by reverse transcriptasepolymerase 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.

Zymosan-induced inflammation stimulates neo-adipogenesis

“…At high doses ZA is recognized to trigger a massive neutrophil-dominated influx of leukocytes when injected into closed spaces in vivo. 29,30 Reducing the dose of ZA avoided this response but even at the lower range of concentrations used in the dose-response assay there was still evidence of a dose-dependent inflammatory effect. Systemically, serum TNF-a levels at early time points were elevated in high ZA dose as compared to low-dose mice and controls.…”

Enhanced suppressor of cytokine signaling 3 in arthritic cartilage dysregulates human chondrocyte function

“…The role of SOCS proteins in mediating inhibition of cytokine and growth factor responses makes the SOCS proteins prime candidates for regulating chondrocyte function during growth and joint diseases. During joint inflammation and after in vivo IL-1 exposure, SOCS-3 is highly expressed in both synovial tissue and chondrocytes (10). In a recent study, we demonstrated that adenoviral overexpression of SOCS-3 caused IGF-1 nonresponsiveness in a murine chondrocyte cell line (6).…”

The JAK/STAT pathway in rheumatoid arthritis: Pathogenic or protective?

“…Alternatively, STAT-1 induces growth arrest and promotes apoptosis in several cell types, including lymphocytes and synovial fibroblasts (30)(31)(32)(33). These functions suggest a protective role for STAT-1 in arthritis, and this possibility is supported by the elevated expression of the STAT-1 proapoptotic target gene caspase-1 in RA synovium (10), and by evidence that STAT-1 deficiency results in exacerbation of experimental arthritis (34). Thus, STAT-1 may have both pathogenic and protective roles in RA synovitis, depending on the cell type and possibly on the stage of disease and the inflammatory microenvironment.…”