Journal
JOURNAL OF PHARMACOLOGICAL SCIENCES
Volume 124, Issue 3, Pages 307-312Publisher
JAPANESE PHARMACOLOGICAL SOC
DOI: 10.1254/jphs.13R18CP
Keywords
arachidonic acid cascade; cytosolic phospholipase A(2)alpha; cyclooxygenase; sphingolipid
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Funding
- Grants-in-Aid for Scientific Research [24790066, 23590106] Funding Source: KAKEN
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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.
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