Vasoactive intestinal peptide inhibits cycloxygenase-2 expression in activated macrophages, microglia, and dendritic cells

Prostaglandin E2 (PGE2) is a potent lipid mediator produced by the inducible form of the enzyme cycloxygenase (COX-2) in inflammatory cells. PGE2 and COX-2 are critical mediators in the pathogenesis of several inflammatory and degenerative diseases, and have therefore emerged as therapeutic targets for the treatment of such disorders. Vasoactive intestinal peptide (VIP) is a well-known anti-inflammatory neuropeptide that protects against several immune disorders by regulating a wide panel of inflammatory mediators. In this work we show the inhibitory effect of VIP on COX-2 expression and subsequent production of PGE2 by macrophages, dendritic cells, and microglia activated with different inflammatory stimuli. This inhibitory effect is exerted at the transcriptional level and mediated through the VIP receptor VPAC1. VIP downregulates NFκB-dependent gene activation of the COX-2 promoter. These findings demonstrate a novel property of VIP that might contribute to their anti-inflammatory effects in vivo, i.e., the inhibition of the inducible COX-2/PGE2 system.