Anti-Inflammatory Role in Septic Shock of Pituitary Adenylate Cyclase-Activating Polypeptide Receptor

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 99; no. 2; pp. 1053 - 1058
• Main Authors: Martinez, Carmen, Abad, Catalina, Delgado, Mario, Arranz, Alicia, Juarranz, Maria G., Rodriguez-Henche, Nieves, Brabet, Philippe, Leceta, Javier, Gomariz, Rosa P.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 22-01-2002; National Acad Sciences; The National Academy of Sciences
• Subjects: Agonists; Animals; Antiinflammatories; Biological Sciences; Cytokines; Endotoxemia; Female; Gene expression regulation; Immunology; Infections; Inflammation - physiopathology; Inflammation - prevention & control; Interleukin-6 - biosynthesis; Lipopolysaccharides - toxicity; Macrophages; Male; Mice; Mice, Knockout; Peptides; Peritoneal macrophages; Receptors; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; Receptors, Pituitary Hormone - deficiency; Receptors, Pituitary Hormone - genetics; Receptors, Pituitary Hormone - physiology; Septic shock; Shock, Septic - physiopathology; Tumor Necrosis Factor-alpha - biosynthesis; Vasoactive Intestinal Peptide - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.012367999

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two mediators synthesized by immune cells, specially under inflammatory and antigen stimulation conditions. Reports have shown that neuropeptides attenuate the deleterious consequences of septic shock both by down-regulating the production of proinflammatory mediators and by stimulating the production of anti-inflammatory cytokines by activated macrophages. In this study, we used a knockout for the PACAP receptor PAC1-/-to demonstrate an important protective role for PAC1 receptor in endotoxic shock. Moreover, our results indicate that PAC1 receptor acts in vivo as an anti-inflammatory receptor, at least in part, by attenuating lipopolysaccharide (LPS)-induced production of proinflammatory IL-6, which appears to be the main cytokine regulating the expression of the majority of the acute phase protein genes, which are an important deleterious component of septic shock. Besides, our findings point to endogenously produced VIP and PACAP as participants of the natural anti-inflammatory machinery. Because VIP and PACAP are two attractive candidates for the development of therapies against acute and chronic inflammatory diseases, septic shock, and autoimmune diseases, this paper represents a contribution to the understanding of the mechanism of action of these anti-inflammatory agents.