IL-32 gamma Induces the Maturation of Dendritic Cells with Th1-and Th17-Polarizing Ability through Enhanced IL-12 and IL-6 Production

Abstract

IL-32, a newly described multifunctional cytokine, has been associated with a variety of inflammatory diseases, including rheumatoid arthritis, vasculitis, and Crohn's disease. In this study, we investigated the immunomodulatory effects of IL-32 gamma on bone marrow-derived dendritic cell (DC)-driven Th responses and analyzed the underlying signaling events. IL-32 gamma-treated DCs exhibited upregulated expression of cell-surface molecules and proinflammatory cytokines associated with DC maturation and activation. In particular, IL-32 gamma treatment significantly increased production of IL-12 and IL-6 in DCs, which are known as Th1- and Th17-polarizing cytokines, respectively. This increased production was inhibited by the addition of specific inhibitors of the activities of phospholipase C (PLC), JNK, and NF-kappa B. IL-32 gamma treatment increased the phosphorylation of JNK and the degradation of both I kappa B alpha and I kappa B beta in DCs, as well as NF-kappa B binding activity to the kappa B site. The PLC inhibitor suppressed NF-kappa B DNA binding activity and JNK phosphorylation increased by IL-32 gamma treatment, thereby indicating that IL-32 gamma induced IL-12 and IL-6 production in DCs via a PLC/JNK/NF-kappa B signaling pathway. Importantly, IL-32 gamma-stimulated DCs significantly induced both Th1 and Th17 responses when cocultured with CD4(+) T cells. The addition of a neutralizing anti-IL-12 mAb abolished the secretion of IFN-gamma in a dose-dependent manner; additionally, the blockage of IL-1 beta and IL-6, but not of IL-21 or IL-23p19, profoundly inhibited IL-32 gamma-induced IL-17 production. These results demonstrated that IL-32 gamma could effectively induce the maturation and activation of immature DCs, leading to enhanced Th1 and Th17 responses as the result of increased IL-12 and IL-6 production in DCs. The Journal of Immunology, 2011, 186: 6848-6859.