In association with impaired IL-10-mediated STAT3 activation, STAT3 was found to be tyrosine phosphorylated persistently (up to 6 hours) in freshly isolated PB and ST CD4+ T cells from RA patients. STAT3 is activated by a variety of cytokines, notably the IL-6 family of cytokines (e.g. IL-6, IL-11, leukemia inhibitory factor, and oncostatin M) and growth factors, in addition to IL-10 [4]. Of these cytokines, IL-6 plays a predominant role in eliciting a systemic reaction such as the acute phase response in active RA, due mainly to its abundance in the blood circulation [27]. Consistent with this notion, IL-6 was the major STAT3-activating factor contained in the serum of active RA patients, and the responsiveness to IL-10 was suppressed in normal CD4+ T cells after 36 hours of incubation with IL-6. These results suggest that both the sustained STAT3 activation and the resistance to IL-10 inhibition found in RA CD4+ T cells may be induced after chronic exposure in vivo to high concentrations of serum IL-6. However, it is also possible that STAT3 activity could be constitutively induced in CD4+ T cells by their own IL-10 secretion, leading to the loss of sensitivity to exogenous IL-10, because RA CD4+ T cells in the ST are capable of producing significant levels of IL-10 [34].