Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit interleukin-12...

The vasoactive intestinal peptide (VIP) and the structurally related neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) act as "macrophage-deactivating factors". We showed previously that VIP and PACAP inhibit the production of macrophage-derived tumor necrosis factor-alpha, interleukin (IL)-6, nitric oxide, and IL-12. This study examines the molecular mechanisms involved in the VIP/PACAP inhibition of IL-12 production. VIP and PACAP inhibit IL-12 (p40) gene expression by affecting both NF-kappaB binding and the composition of the Ets-2 binding complex. Both neuropeptides prevent the activation-induced nuclear translocation of the NF-kappaB components p65 and c-Rel by inhibiting the reduction in cytoplasmic IkappaBalpha. Moreover, VIP and PACAP inhibit the synthesis of the interferon responsive factor-1. The decrease in nuclear interferon responsive factor-1 and c-Rel results in alterations of the Ets-2-binding complex. Two transduction pathways, a cAMP-dependent and a cAMP-independent pathway, are involved in the inhibition of IL-12 gene expression and appear to differentially regulate the transcriptional factors involved. Because IL-12 participates in T cell activation and cytolytic T lymphocyte activity and promotes the differentiation of T helper cells into the Th1 subset, the understanding of the mechanisms that affect IL-12 production in normal and pathological conditions could contribute to immune response-based therapies or vaccine designs.