Spontaneous resolution of acute gouty arthritis is associated with rapid induction of the anti-inflammatory factors TGFβ1, IL-10 and soluble TNF receptors and the intracellular cytokine negative regulators CIS and SOCS3

Objective The molecular basis for spontaneous resolution of acute gouty arthritis (GA) remains unclear. The hypothesis that extracellular and intracellular mechanisms play roles in resolving acute GA was tested. Methods Synovial fluid (SF) levels of transforming growth factor beta 1 (TGF beta 1), interleukin 1 (IL-1) receptor antagonist (IL-1ra), IL-10 and soluble tumour necrosis factor (TNF) receptor I (sTNFRI) and II (sTNFRII) were measured by ELISA in patients with acute GA and osteoarthritis (OA). Monosodium urate (MSU) crystal-stimulated RAW264.7 mouse macrophages were analysed for cytokine inducible SH2-containing protein (CIS) and suppressors of cytokine signalling (SOCS) 1-7 mRNA expression by reverse transcription (RT)-PCR. Immunohistochemical analysis, quantitative PCR and immunoblotting were performed to detect CIS and SOCS3 expression in synovial tissue, SF mononuclear cells (SFMCs) from patients with GA and MSU crystal-stimulated monocyte-derived macrophages from healthy donors. CIS overexpression and small interfering RNA-mediated knockdown in RAW264.7 cells were used to investigate the role of CIS in resolving MSU crystal-induced acute inflammation. Results SF levels of anti-inflammatory molecules TGF beta 1, IL-1ra, IL-10 and sTNFR-I/II were significantly elevated in GA compared to OA. CIS and SOCS3 were upregulated in the synovium and SFMCs from acute GA and MSU crystal-stimulated monocyte-derived macrophages and RAW264.7 cells. CIS overexpression in RAW264.7 cells attenuated MSU crystal-induced IL-1 beta and TNF alpha but enhanced TGF beta 1 production via increased binding of signal transducer and activator of transcription 3 (STAT3) to the TGF beta 1 promoter. Conversely, CIS knockdown reversed the effect of CIS overexpression, resulting in enhanced IL-1 beta and TNF alpha but reduced TGF beta 1 production in MSU crystal-stimulated RAW264.7 cells. Conclusions Increased production of TGF beta 1, IL-1ra, IL-10 and sTNFR-I/II and upregulation of intracellular CIS and SOCS3 expression are associated with spontaneous resolution of acute GA.