Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit endotoxin-induced TNF-alpha production by macrophages: In vitro and in vivo studies

Vasoactive intestinal peptide (VIP) is a neuropeptide synthesized by immune cells that can modulate several immune aspects, including the function of cells involved in the inflammatory response, such as macrophages and monocy tes, The production and release of cytokines by activated phagocytes are im portant events in the pathogenesis of ischemia-reperfusion injury. There is abundant evidence that the proinflammatory cytokine TNF-a is an important mediator of shock and organ failure complicating Gram-negative sepsis, VIP has been shown to attenuate the deleterious consequences of this pathologic phenomenon, In this study we have investigated the effects of VIP and the structurally related neuropeptide pituitary adenylate cyclase-activating po lypeptide (PACAP38) on the production of TNF-alpha by endotoxin-activated m urine peritoneal macrophages. Both neuropeptides rapidly and specifically i nhibit the LPS-stimulated production of TNF-alpha, exerting their action th rough the binding to VPAC1 receptor and the subsequent activation of the ad enylate cyclase system. VIP and PACAP regulate the production of TNF-alpha at a transcriptional level. In vitro results mere correlated with an inhibi tion of both TNF-alpha expression and release in endotoxemic mice in vivo. The immunomodulatory role of VIP in vivo is supported by the up-regulation of VIP release in serum and peritoneal fluid by LPS and proinflammatory cyt okines such as TNF-alpha, IL-1 beta, and IL-6, These findings support the i dea that under toxicity conditions associated with high LPS doses, VIP and PACAP could act as protective mediators that regulate the excessive release of TNF-alpha to reduce inflammation or shock.