Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit interleukin-12 transcription by regulating nuclear factor kappaB and Ets activation.
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.
Delgado
M
M
Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102, USA.
Ganea
D
D
D000818:Animals; D002460:Cell Line; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008934:Mitogens / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism*; D009479:Neuropeptides / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*
C495402:Adcyap1 protein, mouse; D008070:Lipopolysaccharides; D008934:Mitogens; D016328:NF-kappa B; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D014157:Transcription Factors; D018664:Interleukin-12; D014660:Vasoactive Intestinal Peptide; D007371:Interferon-gamma