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 β 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.