text: STAT3 activation has been implicated in the pathogenesis of RA. Active STAT3 is constitutively expressed in synovial fluid mononuclear cells from RA patients [36]. IL-6 is the major STAT3-activating factor present in synovial fluid, which has a crucial role in the activation of monocyte functions such as gene expression of the Fc gamma receptor type I and type III and of HLA-DR [31]. More recently, high levels of activated STAT3, thought to be induced mainly by IL-6, have been detected in the ST, and STAT3 activation has been shown to be involved in synovial fibroblast proliferation and IL-6 production [37]. In this regard, STAT3 is critical in the survival and expansion of growth factor-dependent synovial fibroblasts [38]. Furthermore, the significance of persistent STAT3 signaling in Th1-cell-dominated autoimmune arthritis has been suggested by studies of the gp130F759/F759 mice, in which the Src homology phosphatase-2 binding site of gp130 (the transmembrane glycoprotein beta subunit of the IL-6 family cytokine receptor), tyrosine 759, was mutated to phenylalanine [39]. In the gp130F759/F759 mice, T cells, particularly the CD4+ T-cell subset, are chronically activated and resistant to activation-induced cell death through gp130-mediated STAT3 activation. 
  The longevity of cytokine signals transduced by the JAK-STAT pathway is regulated by the SOCS family proteins [7]. We found that CD4+ T cells from patients with active RA expressed higher levels of SOCS1, but lower levels of SOCS3, compared with normal CD4+ T cells. SOCS1 prevents activation of JAK by directly binding to JAK, and SOCS3 inhibits the action of JAK by binding to the Src homology phosphatase-2-binding domain of receptors such as gp130 [40]. SOCS1 and SOCS3 are induced by various cytokines, including IL-6 and IL-10, as mediators of negative feedback and crosstalk inhibition [7]. Recent studies with mice lacking SOCS3 or SOCS1 revealed that SOCS3 is a negative regulator of IL-6 signaling but not of IL-10 signaling. Studies of conditional SOCS3-deficient mice have shown that SOCS3 deficiency, but not SOCS1 deficiency, results in sustained activation of STAT3 in response to IL-6 [8,41]. The analysis of SOCS3-deficient macrophages has indicated that SOCS3 is a crucial inhibitor of the IL-6-induced transcriptional response [42]. However, SOCS3 is dispensable for both the negative feedback inhibition and the immunoregulatory action of IL-10 in macrophages [41]. On the contrary, SOCS1 was found to directly inhibit IL-10-mediated signaling [43]. Increased SOCS1 expression in RA CD4+ T cells may therefore be associated with both the impaired responsiveness to IL-10 and to IL-10-mediated STAT3 activation, and defective SOCS3 expression may be responsible for persistent STAT3 activation in response to serum IL-6. 
  There is a possibility that SOCS1 induction may be associated with the ability of CD4+ T cells to produce IFN-gamma, because CD4+ T cells from active RA could produce high levels of IFN-gamma in the presence of IL-10, and because IFN-gamma has been known as a potent inducer of SOCS1 [32]. It is of interest in this regard to indicate that polarized Th1 and Th2 cells express high levels of SOCS1 and SOCS3 mRNA, respectively [44]. IL-12-induced STAT4 activation is inhibited by SOCS3 induction in Th2 cells, whereas IL-4-induced STAT6 signaling is diminished by SOCS1 induction in Th1 cells. SOCS1 and SOCS3 may thus have important roles as Th1-specific and Th2-specific, mutually exclusive, cross-talk repressors of the IL-4-STAT6 and the IL-12-STAT4 signaling pathways, respectively. Consistent with this notion, PB T cells from patients with allergic diseases significantly express high levels of SOCS3 transcripts, and the SOCS3 expression correlates well with serum IgE levels and disease pathology [45]. Higher SOCS1 expression with lower SOCS3 expression in PB CD4+ T cells from RA patients, compared with healthy controls, is therefore probably consistent with their systemic bias towards a Th1 phenotype, as has previously been demonstrated [46-49]. 
  