THE VASOACTIVE PEPTIDE MAXADILAN FROM SAND FLY SALIVA INHIBITS TNF-ALPHA AND INDUCES IL-6 BY MOUSE MACROPHAGES THROUGH INTERACTION WITH THEPITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE (PACAP) RECEPTOR

Maxadilan is a vasodilatory peptide encoded by a gene cloned from Lutz omyia longipalpis salivary glands. In this study rye investigated the effects of maxadilan on macrophage functions. Maxadilan treatment of L PS-stimulated BALB/c macrophages inhibited TNF-alpha release but incre ased IL-6, Further, it also induced IL-6 release in a dose-dependent m anner from unstimulated macrophages, Maxadilan increased production of PGE(2), and the inhibition of TNF-alpha was completely abrogated by i ndomethacin, Others have recently shown that maxadilan is a selective agonist of the pituitary adenylate cyclase-activating polypeptide (PAC AP) type I receptor, Treatment with the receptor antagonist PACAP 6-38 blocked maxadilan activities on macrophages, The natural endogenous l igand, PACAP 38, had the same effects as maxadilan on TNF-alpha and IL -6 production. Finally, in a dose- and time-dependent fashion, maxadil an induced the intracellular accumulation of cAMP in macrophages. Take n together, the results presented here indicate a modulatory effect of ligands of PACAP type I receptor on cytokine production by macrophage s and suggest that activation of this receptor, with the subsequent el evation of intracellular cAMP in macrophages, could participate in a n egative-feedback mechanism that controls certain inflammatory response s.