Inhibition of endotoxin-induced macrophage chemokine production by vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide in vitro and in vivo

Inflammatory chemokines recruit various populations of immune cells that in itiate and maintain the inflammatory response against foreign Ags. Although such a response is necessary for the elimination of the Ag, the inflammati on has to be eventually resolved in a healthy organism. Neuropeptides such as vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-acti vating polypeptide (PACAP), released after antigenic stimulation, contribut e to the termination of an inflammatory response primarily by inhibiting th e production of proinflammatory cytokines. Here we investigated the effects of VIP and PACAP on chemokine production. We report that VIP and PACAP inh ibit the expression of the macrophage-derived CXC chemokines macrophage inf lammatory protein-2 and KC (IL-8), and of the CC chemokines MIP-1 alpha, MI P-1 beta, monocyte chemoattractant protein 1, and RANTES in vivo and in vit ro. The inhibition of chemokine gene expression correlates with an inhibito ry effect of VIP/PACAP on NF-kappaB binding and transactivating activity. T he VIP/PACAP inhibition of both chemokine production and of NF-kappaB bindi ng and transactivating activity is mediated through the specific VIP recept or VPAC1, and involves both cAMP-dependent and -independent intracellular p athways. In an in vivo model of acute peritonitis, the inhibition of chemok ine production by VIP/PACAP leads to a significant reduction in the recruit ment of polymorphonuclear cells, macrophages, and lymphocytes into the peri toneal cavity. These findings support the proposed role of VIP and PACAP as key endogenous anti-inflammatory agents and describe a novel mechanism, i. e., the inhibition of the production of macrophage-derived chemokines.