We next examined whether IL-6 could suppress the effect of IL-10 to inhibit IFN-γ production by CD4+ T cells. After preincubation with or without 10 ng/ml IL-6 for 36 hours, normal CD4+ T cells were stimulated by CD3 and CD28 costimulation in the presence or absence of 1 ng/ml IL-10 for 36 hours, and the IFN-γ production was measured by ELISA. IL-6 pretreatment of normal cells reduced IL-10-mediated inhibition of IFN-γ production (Fig. 5b), indicating that high concentrations of IL-6 could modulate T-cell responsiveness to IL-10. Taken together, these findings suggest that persistent exposure to serum IL-6 may have a role in both the induction of STAT3 activation and the resistance to the inhibitory effect of IL-10 in RA CD4+ T cells.