CD4+ T cells isolated from the ST of RA also showed a defect in the IL-10-induced STAT3 signaling pathway. It is most probable that the resistance of CD4+ T cells to IL-10 can be even augmented after migration into the inflamed ST, because IL-6 is highly concentrated compared with the blood level [27]. In addition, the involvement of other essential proinflammatory cytokines in this process was suggested by our preliminary experiments demonstrating that IL-10-mediated IFN-γ inhibition in CD4+ T cells was reduced by pretreatment with IL-1β and TNF-α, although less effectively than by IL-6 (data not shown). Furthermore, IFN-γ and IL-10 produced by CD4+ T cells themselves could be responsible for impaired IL-10 signaling in the ST, because T-cell infiltrates produce both cytokines [34,35]. In an autocrine fashion, IL-10 may persistently stimulate STAT3 activation and IFN-γ can induce SOCS1 protein as a crosstalk inhibitor of IL-10 signaling [32]. The T-cell-inhibitory effect of IL-10 may therefore be modulated complicatedly upon exposure to an inflammatory environment in RA joints, where many cytokines are present substantially [10].