THE PACAP-TYPE I RECEPTOR AGONIST MAXADILAN FROM SAND FLY SALIVA PROTECTS MICE AGAINST LETHAL ENDOTOXEMIA BY A MECHANISM PARTIALLY DEPENDENT ON IL-10

Sand fly saliva contains maxadilan, a peptide that causes vasodilation and modifies the secretion of pro-inflammatory cytokines by macrophag es. We show that 1 to 10 mu g maxadilan protected BALB/c mice against a lethal dose of LPS. Maxadilan reduced serum levels of TNF-alpha by a pproximately tenfold, while it caused a threefold increase in IL-6 and IL-10. The protective effect of maxadilan is partially dependent on i ts ability to induce IL-10 production since maxadilan did not prevent death from endotoxic shock in IL-10(-/-) mice. Finally, maxadilan is a selective agonist of the pituitary adenylate cyclase-activating pepti de (PACAP) type I receptor, and we found that the natural ligand of th is receptor (PACAP 38) also protected mice against lethal endotoxemia. These results indicate that activation of the PACAP type I receptor m ay contribute to the control of systemic inflammation by a mechanism t hat is partially dependent on IL-10.