Two-sided roles of IL-27: Induction of Th1 differentiation on naive CD4⁺ T cells versus suppression of proinflammatory cytokine production including IL-23-induced IL-17 on activated CD4⁺ T cells partially through STAT3-dependent mechanism

Recent lines of evidence have demonstrated that IL-27, a newly identified IL-12-related cytokine, has two apparently conflicting roles in immune responses: one as an initiator of Th1 responses and the other as an attenuator of inflammatory cytokine production. Although the BL-27-mediated Th1 initiation mechanism has been elucidated, little is known about the molecular basis for the suppression of cytokine production. In the present study, we demonstrated that IL-27 suppressed the production of various proinflammatory cytokines by fully activated CD4⁺ T cells while it had no effect on the cytokine production by CD4⁺ T cells at early phases of activation. IL-27 also suppressed IL-17 production by activated CD4⁺ T cells, thereby counteracting IL-23, another IL-12-related cytokine with proinflammatory effects. In fully activated CD4⁺ T cells, STAT3 was preferentially activated by IL-27 stimulation, whereas both STAT1 and 3 were activated by IL-27 in early activated CD4⁺ T cells. Lack of STAT3 in fully activated cells impaired the suppressive effects of IL-27. These data indicated that the preferential activation of STAT3 in fully activated CD4⁺ T cells plays an important role in the cytokine suppression by IL-27/WSX-1.