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Vasoactive intestinal peptide (VIP)is a novel Th2 cytokine that has been shown previously to rescue rats and mice from the lethal effect of bacterial lipopolysaccharide (LPS). We report that VIP inhibited production of the proinflammatory cytokines, tumor necrosis factor-α(TNF-α)and interleukin-1β (IL-1β), at the mRNA level and that the inhibitory effect of VIP was maintained when macrophages were cocultured with an immunostimulatory concentration of interferon-γ (IFN-γ)(100 U/ml). The concentration of VIP that had optimal inhibitory effect was ^10–10 M. Furthermore, VIP prevented macrophage killing of a phoP mutant of Salmonella enterica serovar typhimurium, which is usually attenuated for virulence as a result of its inability to survive inside macrophages. However, although the effect of VIP on inducible nitric oxide synthase (iNOS) was less clear, N-monoethyl arginine (NEMA)(an iNOS inhibitor)did not rescue S. typhimurium from IFN- γ-induced death, in accordance with previous reports that suggest that iNOS is not an important Salmonella killing pathway in macrophages within the first 24 h. VIP is a potent inhibitor of inflammatory pathways that lead to significant pathologic conditions. However, it increases survival of the normally avirulent phoP mutant and is able to inhibit IFN-γ-stimulated killing of wild-type S. typhimurium in murine macrophages. Thus, VIP inhibits the proinflammatory type 1 response, thus favoring Salmonella survival.