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.