PMC:1064873 / 1680-7010 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/1064873","sourcedb":"PMC","sourceid":"1064873","source_url":"http://www.ncbi.nlm.nih.gov/pmc/1064873","text":"Introduction\nIL-10 is a key cytokine in regulating inflammatory responses, mainly by inhibiting the production and function of proinflammatory cytokines. IL-10 binds to the IL-10 receptor (IL-10R) complex that is composed of two subunits, the primary ligand-binding component type 1 IL-10R (IL-10R1) and the accessory component type 2 IL-10R [1]. The interaction of IL-10 and IL-10R engages the Janus kinase (JAK) family tyrosine kinases Jak1 and Tyk2, which are constitutively associated with IL-10R1 and type 2 IL-10R, respectively [2]. IL-10 induces tyrosine phosphorylation and activation of the latent transcriptional factors signal transducer and activator of transcription (STAT) 3 and STAT1 [3]. Upon phosphorylation, STAT1 and STAT3 proteins form homodimers or heterodimers, rapidly translocate into the nucleus, and modulate gene transcription. Intriguingly, STAT3 is indispensable for both IL-10-derived anti-inflammatory and IL-6-derived proinflammatory responses [4]. Studies of cell-type-specific STAT3-deficient mice have shown that STAT3 activation is essential for IL-10-mediated anti-inflammatory reactions in macrophages and neutrophils [5], but is responsible for IL-6-mediated prevention of apoptosis in T cells [6]. The suppressor of cytokine signaling (SOCS) proteins have been identified as a family of endogenous JAK kinase inhibitors that can act in classic feedback inhibition loops, but their roles as the mediators of crosstalk inhibition by opposing cytokine signaling pathways have been clarified [7]. Recent studies indicate that SOCS3 plays a key role in regulating the divergent action of IL-10 and IL-6, by specifically blocking STAT3 activation induced by IL-6 but not that induced by IL-10 [8,9].\nThe synovial membrane of rheumatoid arthritis (RA) is characterized by an infiltrate of a variety of inflammatory cells, such as lymphocytes, macrophages, and dendritic cells, together with proliferation of synovial fibroblast-like cells. Numerous cytokines are overproduced in the inflamed joint, and macrophages and synovial fibroblasts are an important source of proinflammatory cytokines. Tumor necrosis factor alpha (TNF-α) and IL-1, two major macrophage products, are crucial in the process of chronic inflammation and joint destruction, and they give rise to effector components, including other inflammatory cytokines, chemokines, growth factors, matrix proteases, nitric oxide, and reactive oxygen species [10]. IL-6 is a pleiotropic cytokine produced substantially by activated fibroblasts, and its proinflammatory actions include simulating the acute-phase response, B-cell maturation into plasma cells, T-cell functions, and hematopoietic precursor cell differentiation [11].\nHowever, anti-inflammatory cytokines and cytokine inhibitors are also present in large quantities in RA joints. IL-10, produced by macrophages and partly by T cells in the synovial tissue (ST), is best known as a negative regulator for macrophage and Th1 cells, but the expression level is insufficient to counterbalance the cascade of proinflammatory events [12]. In addition, the anti-inflammatory action of IL-10 appears to be modulated at the level of signal transduction during chronic inflammation. IL-10 signaling is impaired in macrophages upon chronic exposure to proinflammatory cytokines such as TNF-α and IL-1 and immune complexes [13,14]. Cell surface expression of IL-10R1 is decreased in synovial fluid dendritic cells due to the presence of TNF-α, IL-1, and granulocyte–macrophage colony-stimulating factor [15].\nCD4+ T cells may be activated by arthritogenic antigens, in conjunction with CD28-mediated costimulatory signaling, in RA. The significance of this autoimmune process has been supported by the linkage of the MHC class II antigens HLA-DRB1*0404 and HLA-DRB1*0401 with disease susceptibility and severity [16,17], and by the high-level expression of MHC class II molecules and both CD28 ligands, CD80 and CD86, in the inflamed ST [18-20]. The continuing emergence of activated CD4+ T cells, even though few in number, may be crucial in sustaining the activation of macrophages and synovial fibroblasts through cell surface signaling by means of cell surface CD69 and CD11, as well as the release of proinflammatory Th1 cytokines such as interferon gamma (IFN)-γ and IL-17 [21,22]. In addition, CD4+ T cells could stimulate B-cell production of autoantibodies such as rheumatoid factor and osteoclast-mediated bone destruction. Their obligatory role in RA synovitis was recently proved by successful treatment of active disease by selective inhibition of T-cell activation with fusion protein of cytotoxic T-cell-associated antigen 4 (CD152)-IgG, which can block the engagement of CD28 on T cells by binding to CD80 and CD86 with high avidity [23].\nIL-10 efficiently blocks the antigen-specific T-cell cytokine response by inhibiting the CD28 signaling pathway [24], as well as indirectly by downregulating the function of antigen-presenting cells. To elucidate the resistance of CD4+ T cells to this direct inhibition in RA, we investigated the production of IFN-γ after CD3 and CD28 costimulation in the presence of IL-10, the induction of STAT1 and STAT3 phosphorylation by IL-10, and the expression of SOCS1 and SOCS3 mRNA in peripheral blood (PB) CD4+ T cells from RA 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