Cyclooxygenase-2 Mediated Oxidation of 2-Arachidonoyl-Lysophospholipids Identifies Unknown Lipid Signaling Pathways

Eicosanoid lipids play important roles in cellular signaling as second messengers in inflammation, immune response, vascular tone, and the CNS. Biosynthesis of eicosanoid lipids proceeds via hydrolysis of esterified arachidonic acid from phospholipids followed by oxidation of the released arachidonic acid by a variety of enzymes including cyclooxygenases (COX). Herein, we demonstrate the remarkable ability of COX-2, but not COX-1, to directly oxidize 2-arachidonoyl-lysolipids, resulting in the generation of previously unknown classes of eicosanoid-lysolipids, and provide evidence that intracellular lipases can release eicosanoids from their eicosanoid-lysolipid precursors. Importantly, genetic ablation of a phospholipase, iPLA2γ, significantly reduced the amounts of these eicosanoid-lysolipids in murine hepatic tissue and fibroblasts. Furthermore, calcium stimulation of wild-type murine lung fibroblasts produced robust increases in these eicosanoid-lysolipids, which were markedly attenuated in iPLA2γ−/− fibroblasts. Collectively, these results identify an iPLA2γ-initiated pathway generating new classes of lipid metabolites with potential signaling functions resulting from the direct COX-2 catalyzed oxidation of 2-arachidonoyl-lysolipids. [Display omitted] •COX-2 directly oxidizes 2-arachidonoyl-lysophospholipids to eicosanoid-lysolipids•Lipases (e.g., cPLA2α) release eicosanoids from eicosanoid-lysolipid precursors•Genetic ablation of iPLA2γ reduces the amounts of eicosanoid-lysolipids•Calcium stimulation robustly increases the production of eicosanoid-lysolipids Liu et al. demonstrate the previously unrecognized ability of COX-2, but not COX-1, to directly oxidize 2-arachidonoyl-lysolipids produced by iPLA2γ to generate multiple novel eicosanoid-lysolipids that can be hydrolyzed by known intracellular lipases (e.g., cPLA2α) to generate non-esterified eicosanoids.