title: Role of sphingolipids in arachidonic acid metabolism.
abstract: The arachidonic acid (AA) cascade is regulated mainly by the actions of two rate-limiting enzymes, phospholipase A₂ (PLA₂) and inducible cyclooxygenase-2 (COX-2). PLA₂ 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 PLA₂ family, cytosolic PLA₂α (cPLA₂α, 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 cPLA₂α directly, sphingosine-1-phosphate induces COX-2 expression. Sphingomyelin has been shown to inhibit the activity of cPLA₂α. In addition, several sphingolipid analogs including a therapeutic agent currently used clinically are also reported to be inhibitors of cPLA₂α. This review explores the role of sphingolipids in the regulation of cPLA₂α and COX-2.
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Murayama
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002478:Cells, Cultured; D002518:Ceramides / Q000494:pharmacology / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D000068876:Fingolimod Hydrochloride; D006056:Golgi Apparatus / Q000378:metabolism; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007790:Lactosylceramides / Q000494:pharmacology / Q000502:physiology; D008246:Lysophospholipids / Q000494:pharmacology / Q000502:physiology; D011409:Propylene Glycols / Q000494:pharmacology; D013107:Sphingolipids / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D013109:Sphingomyelins / Q000494:pharmacology / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology
chemical_list: D002518:Ceramides; D007790:Lactosylceramides; D008246:Lysophospholipids; D011409:Propylene Glycols; D013107:Sphingolipids; D013109:Sphingomyelins; C065576:ceramide 1-phosphate; C060506:sphingosine 1-phosphate; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; D054513:Group IV Phospholipases A2; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine