Numerous cytokines, both proinflammatory and anti-inflammatory, have been detected in the ST of RA, and the balance between these opposing cytokine activities regulates disease severity [10]. Endogenous IL-10, produced mainly by macrophages and T cells, inhibits proinflammatory cytokine production by ST cells [12]. However, this regulatory activity seems to be restricted during chronic inflammation. The activation of both the extracellular stimulus-regulated kinase and p38 kinase pathways, induced by TNF-α and IL-1, inhibits the Jak1–STAT3 signaling pathway shared by IL-10 and IL-6 in adhered macrophages [13]. More importantly, IL-10-mediated STAT3 activation is mostly undetectable in RA synovial macrophages. This impaired IL-10 signaling is probably induced by chronic exposure to immune complexes in vivo, because both cell surface IL-10R1 expression and IL-10-induced Jak1 activation are suppressed in IFN-γ-primed macrophages by a protein kinase C-dependent pathway following ligation of the IgG Fc gamma receptor [14]. Furthermore, dendritic cells from RA synovial fluids are resistant to the immunoregulatory effect of IL-10 due to decreased transport of intracellular IL-10R1 in the presence of proinflammatory cytokine stimuli such as TNF-α, IL-1, and granulocyte–macrophage colony-stimulating factor [15]. We have demonstrated that the resistance of RA CD4+ T cells to IL-10 may be associated with defective IL-10-dependent STAT3 activation, but not with IL-10R1 expression. Inhibitory effects of IL-10 on these inflammatory cell types are therefore differentially modulated at the signal transduction level under the inflammatory environment in RA.