Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit LPS-stimulated MIP-1alpha production and mRNA expression.
Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are neuropeptides with immunomodulatory properties, including the regulation of several proinflammatory mediators. Such mediators, for example chemokines, influence trafficking of inflammatory cells and contribute to shaping the immune response. In the present work, we studied the effect of VIP and PACAP on the CC chemokine macrophage inflammatory protein-1 alpha (MIP-1alpha) production in LPS-stimulated RAW 264.7 macrophage cell line. VIP and PACAP inhibited the production of MIP-1alpha in a dose-dependent manner and over a broad spectrum of LPS concentrations. The use of selective agonists and antagonists of VIP/PACAP receptors showed that type 1 VIP receptor (VPAC1) is the major receptor involved, but the type 2 VIP receptor (VPAC2) may be also implicated. By using selective PKA and PKC inhibitors and cAMP mimicked agents, we demonstrated a cAMP-dependent signalling pathway for the inhibitory effect of VIP/PACAP on MIP-1alpha production, although a minor non-mediated cAMP pathway was also involved. mRNA expression studies showed a down-regulation of MIP-1alpha gene expression by VIP and PACAP. Taken together, the present work strongly supports an anti-inflammatory role of VIP and PACAP by a new mechanism associated with impairment of a key component of the chemokine network.
Pozo
David
D
Department of Medical Biochemistry and Molecular Biology, The University of Seville School of Medicine, Sevilla, Spain.
Guerrero
Juan M
JM
Calvo
Juan R
JR
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D008070:Lipopolysaccharides / Q000378:metabolism*; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism*; D051379:Mice; D009479:Neuropeptides / Q000378:metabolism* / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism*
C495402:Adcyap1 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012333:RNA, Messenger; D014660:Vasoactive Intestinal Peptide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C