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 macrophages. We show that 1 to 10 microg maxadilan protected BALB/c mice against a lethal dose of LPS. Maxadilan reduced serum levels of TNF-alpha by approximately tenfold, while it caused a threefold increase in IL-6 and IL-10. The protective effect of maxadilan is partially dependent on its 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 peptide (PACAP) type I receptor, and we found that the natural ligand of this receptor (PACAP 38) also protected mice against lethal endotoxemia. These results indicate that activation of the PACAP type I receptor may contribute to the control of systemic inflammation by a mechanism that is partially dependent on IL-10.
Bozza
M
M
Department of Tropical Public Health, Harvard School of Public Health, Boston, USA. mbozza@gene.dbbm.fiocruz.br
Soares
M B
MB
Bozza
P T
PT
Satoskar
A R
AR
Diacovo
T G
TG
Brombacher
F
F
Titus
R G
RG
Shoemaker
C B
CB
David
J R
JR
D000818:Animals; D019446:Endotoxemia / Q000139:chemically induced / Q000517:prevention & control*; D005688:Galactosamine / Q000494:pharmacology; D019476:Insect Proteins / Q000494:pharmacology*; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics / Q000276:immunology*; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D015539:Platelet Activation / Q000187:drug effects; D011576:Psychodidae / Q000737:chemistry; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011979:Receptors, Pituitary Hormone / Q000819:agonists*; D012471:Salivary Proteins and Peptides / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C495402:Adcyap1 protein, mouse; D019476:Insect Proteins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011979:Receptors, Pituitary Hormone; D012471:Salivary Proteins and Peptides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C069147:maxadilan protein, insect; D005688:Galactosamine