Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit the production of inflammatory mediators by activated microglia.
Microglia play a central role in the regulation of immune and inflammatory activities, as well as tissue remodeling in the central nervous system. However, activation of microglia is a histopathological hallmark of several neurodegenerative diseases. Pathological microglial activation is believed to contribute to progressive damage in neurodegenerative diseases through the release of proinflammatory and/or cytotoxic factors, including tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, IL-12, and nitric oxide (NO). Hence, it is important to unravel mechanisms regulating microglia activation of inflamed brain parenchyma to provide insights into efficient therapeutic intervention. This study examines the role of two anti-inflammatory neuropeptides, the vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP) on the production of various proinflammatory factors by endotoxin-stimulated microglia. VIP and PACAP inhibit TNF-alpha, IL-1beta, IL-6, and NO production by lipopolysaccharide (LPS)-activated microglia. The specific type 1 VIP receptor mediates the inhibitory effect of VIP/PACAP, and cyclic adenosine monophosphate is the major, second messenger involved. VIP and PACAP regulate the production of these proinflammatory factors at a transcriptional level by inhibiting p65 nuclear translocation and nuclear factor-kappaB-DNA binding. This effect is mediated, as neuropeptides stabilize the inhibitor IkappaB by inhibiting LPS-induced IkappaB-kinase activity. Therefore, the inhibitory effects on the production of proinflammatory mediators define VIP and PACAP as "microglia-deactivating factors" with significant, therapeutical potential for inflammatory/degenerative brain disorders.
Delgado
Mario
M
Department of Biological Sciences, Rutgers University, Newark, New Jersey, USA. mariodm@bio.ucm.es
Leceta
Javier
J
Ganea
Doina
D
D000818:Animals; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009479:Neuropeptides / Q000494:pharmacology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D018005:Receptors, Vasoactive Intestinal Peptide / Q000502:physiology; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*; D000093242:Interleukin-6 Inhibitors
D018836:Inflammation Mediators; D007375:Interleukin-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009479:Neuropeptides; D009569:Nitric Oxide; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D018005:Receptors, Vasoactive Intestinal Peptide; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D014409:Tumor Necrosis Factor-alpha; D014660:Vasoactive Intestinal Peptide; D000093242:Interleukin-6 Inhibitors; C495402:Adcyap1 protein, mouse