IL-17 is an important cytokine involved in multiple inflammatory diseases partially through the up-regulation of various pro-inflammatory cytokines and chemokines. The regulation of IL-17 production has been well studied, but the role of OX40 on IL-17 regulation has not been fully illustrated. In this study, we investigated the effect of activation of OX40 on IL-17 production. As expected, stimulation of PHA activated human peripheral blood mononuclear cells (PBMCs) with soluble OX40L increased both Th1 (IFNγ) and Th2 (IL-4 and IL-13) cytokine production. However, addition of soluble OX40L significantly inhibited IL-17 production, and this inhibition was abrogated by IFNγ mAb. IL-23 is a major stimulator for IL-17 and IL-23 enhanced IL-17 production was also inhibited by soluble OX40L in purified human CD4 and CD8 T cells. The downregulation of IL-17 by activation of OX40 was also demonstrated in murine splenocytes from OVA TCR transgenic mice. Blockage of OX40/OX40L interaction with either OX40L antibody or mouse OX40/Fc protein enhanced IL-17 production. In addition, agonistic OX40 antibody inhibited antigen induced IL-17 production and antagonistic OX40 antibody enhanced IL-17 production in splenocytes from OVA transgenic mice. Taken together, our results show that activation of OX40 exerts a negative regulation on IL-17 production. The inhibition is probably mediated through the up regulation of IFNγ production.
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