Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation

Abstract

Prostaglandins, leukotrienes, platelet-activating factor, lysophosphatidic acid, sphingosine 1-phosphate, and endocannabinoids, collectively referred to as lipid mediators, play pivotal roles in immune regulation and self-defense, and in the maintenance of homeostasis in living systems. They are produced by multistep enzymatic pathways, which are initiated by the de-esterification of membrane phospholipids by phospholipase A2s or sphingo-myelinase. Lipid mediators exert their biological effects by binding to cognate receptors, which are members of the G protein-coupled receptor superfamily. The synthesis of the lipid mediators and subsequent induction of receptor activity is tightly regulated under normal physiological conditions, and enzyme and/or receptor dysfunction can lead to a variety of disease conditions. Thus, the manipulation of lipid mediator signaling, through either enzyme inhibitors or receptor antagonists and agonists, has great potential as a therapeutic approach to disease. In this review, I summarize our current state of knowledge of the synthesis of lipid mediators and the function of their cognate receptors, and discuss the effects of genetic or pharmacological ablation of enzyme or receptor function on various pathophysiological processes.