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Vasoactive intestinal peptide and pituitary adenylate cyclase‐activating polypeptide inhibit the production of inflammatory mediators by activated microglia
Author(s) -
Delgado Mario,
Leceta Javier,
Ganea Doina
Publication year - 2003
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0702372
Subject(s) - proinflammatory cytokine , vasoactive intestinal peptide , microglia , biology , tumor necrosis factor alpha , pituitary adenylate cyclase activating peptide , endocrinology , inflammation , medicine , neuropeptide , immunology , receptor , biochemistry
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 α (TNF‐α), interleukin (IL)‐1β, 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 miroglia. VIP and PACAP inhibit TNF‐α, IL‐1β, 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‐κB‐DNA binding. This effect is mediated, as neuropeptides stabilize the inhibitor IκB by inhibiting LPS‐induced IκB‐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.