The Role of Sphingolipids in Arachidonic Acid Metabolism

The arachidonic acid (AA) cascade is regulated mainly by the actions of two rate-limiting enzymes,.phospholipase A(2) (PLA(2)) and inducible cyclooxygenase-2 (COX-2). PLA(2) acts to generate AA, which serves as the precursor substrate for COX-2 in the metabolic pathway leading to prostaglandin production. Amongst more than 30 members of the PLA(2) family, cytosolic PLA(2)alpha (cPLA(2)alpha, group IVA) plays a major role in releasing AA from cellular membranes. Sphingolipids are a novel class of bioactive lipids that play key roles in the regulation of several cellular processes including growth, differentiation, inflammatory responses, and apoptosis. Recent studies implicated a regulatory function of sphingolipids in prostaglandin production. Whereas ceramide-1-phosphate and lactosylceramide activate cPLA(2)alpha directly, sphingosine-1-phosphate induces COX-2 expression. Sphingomyelin has been shown to inhibit the activity of cPLA(2)alpha. In addition, several sphingolipid analogs including a therapeutic agent currently used clinically are also reported to be inhibitors of cPLA(2)alpha. This review explores the role of sphingolipids in the regulation of cPLA(2)alpha and COX-2.