The cardinal role of the phospholipase A(2)/cyclooxygenase-2/prostaglandin E synthase/prostaglandin E(2) (PCPP) axis in inflammostasis

Abstract

The process of inflammation is regulated in part by bioactive lipids of which prostaglandins/eicosanoids form an important class. We provide evidence that the phospholipase A(2)/cyclooxygenase-2/prostaglandin E synthase/prostaglandin E(2) (PCPP) axis is positioned at the core of a natural regulatory circuit controlling the initiation, magnitude, duration, and resolution of the inflammatory response. During the inflammatory phase, proinflammatory cytokine, chemokine and matrix destructive metalloprotease expression levels are moderated by the PCPP axis through the modulation of signaling pathways that control proinflammatory gene expression at transcriptional, post-transcriptional, and translational levels. The PCPP axis also contributes to the activation of lipid mediator class switching; this highly coordinated process results in the biosynthesis of lipoxins and resolvins that promote inflammatory resolution through a variety of cellular and molecular mechanisms. The PCPP axis activity is autoregulated by way of a positive feedback circuit involving PGE(2)-mediated, p38 MAPK-dependent stabilization of COX-2 mRNA and COX-2 catalytic potentiation via its limited proteolytic cleavage (e.g., Ca(2+)-activated calpains). In conclusion, through its fine temporal modulation of multiple signaling cassettes via EP1-EP4 GPCRs, PGE(2) influences the onset, course, magnitude, and duration of the inflammatory response and functions as a key feedback regulator of the cellular and molecular processes controlling inflammation.