Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide enhance IL-10 production by murine macrophages: In vitro and in vivo studies

Vasoactive intestinal peptide (VIP), a neuropeptide present in the lymphoid microenvironment, and the structurally related pituitary adenylate cyclase -activating polypeptide (PACAP) act as potent anti-inflammatory agents that inhibit the function of activated macrophages and TR cells, Previous repor ts showed that VIP/PACAP inhibit IL-6 and TNF-alpha production in LPS-stimu lated macrophages. The present study reports on the effect of VLP/PACAP on IL-10 production, Although VIP/PACAP do not induce IL-IO by themselves, the y enhance IL-10 production in LPS-stimulated macrophages. The specific VPAC 1 receptor mediates the stimulatory effect of VIP/PACAP, and cAMP is the ma jor second messenger involved. VIP/PACAP increase IL-10 mRNA in LPS-stimula ted cells, and the effect of transcriptional and protein synthesis inhibito rs indicates de novo IL-10 production. Electromobility shift assays show th at VIP/PACAP induce an increase in nuclear cAMP response element (CRE)-bind ing complexes, with CRE binding protein as the major active component. Trea tments with either a VPAC1 antagonist or a protein kinase A inhibitor aboli sh IL-10 stimulation and, concomitantly, the increase in CRE binding. Effec ts similar to the in vitro stimulation of IL-10 were obtained in vivo in mi ce treated with LPS and VIP or PACAP, The neuropeptides induce increased le vels of IL-10 in both serum and peritoneal fluid, and increased expression of the IL-IO mRNA in peritoneal exudate cells. The stimulation of IL-10 pro duction in activated macrophages represents a novel anti-inflammatory activ ity of VIP and PACAP, which presumably acts in vivo in conjunction with the inhibition of proinflammatory cytokines such as IL-6 and TNF-alpha to redu ce the magnitude of the immune response.