Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit interleukin-12 transcription by regulating nuclear factor kappa B and Ets activation

The vasoactive intestinal peptide (VIP) and the structurally related neurop eptide pituitary adenylate cyclase-activating polypeptide (PACAP) act as "m acrophage-deactivating factors". We showed previously that VIP and PACAP in hibit the production of macrophage-derived tumor necrosis factor-alpha, int erleukin (LL)-6, nitric oxide, and IL-12. This study examines the molecular mechanisms involved in the VIP/PACAP inhibition of IL-12 production. VIP a nd PACAP inhibit IL-12 (p40) gene expression by affecting both NF-kappa B b inding and the composition of the Ets-2 binding complex. Both neuropeptides prevent the activation-induced nuclear translocation of the NF-kappa B com ponents p65 and c-Rel by inhibiting the reduction in cytoplasmic I kappa B alpha, Moreover, VIP and PACAP inhibit the synthesis of the interferon resp onsive factor-1. The decrease in nuclear interferon responsive factor-1 and c-Rel results in alterations of the Ets-S-binding complex. Two transductio n pathways, a cAMP-dependent and a cAMP-independent pathway, are involved i n the inhibition of IL-12 gene expression and appear to differentially regu late the transcriptional factors involved. Because IL-12 participates in T cell activation and cytolytic T lymphocyte activity and promotes the differ entiation of T helper cells into the Th1 subset, the understanding of the m echanisms that affect IL-12 production in normal and pathological condition s could contribute to immune response-based therapies or vaccine designs.