Cyclooxygenase-2 is induced in monocytes by peroxisome proliferator activated receptor gamma and oxidized alkyl phospholipids from oxidized low density lipoprotein.
Low density lipoprotein (LDL) oxidation and monocyte infiltration of the vessel wall underlie atherogenesis. These cells express cyclooxygenase-2, but the way oxidized LDL stimulates cyclooxygenase-2 transcription is unknown. Oxidized LDL, oxidatively fragmented phospholipids isolated from oxidized LDL, a synthetic oxidized alkylphospholipid (azPC) that is a potent peroxisome proliferator activated receptor (PPAR) gamma agonist, or the PPARgamma agonist rosiglitazone all induced cyclooxygenase-2 expression and enhanced prostaglandin E(2) (PGE(2)) secretion in primary human monocytes. The cyclooxygenase-2 inhibitor NS398 blocked PPARgamma-induced PGE(2) secretion. Phospholipase A(1) and A(2) digestion shows that oxidized alkylphospholipids, and not oxidized fatty acids, were the relevant agonists. The upstream PPAR-responsive element (PPRE) of cyclooxygenase-2 was required for induction of a luciferase reporter by oxidized phospholipids, azPC, and rosiglitazone, and a ( COX-2 PPRE)(3)-luciferase reporter was responsive to these PPARgamma agonists. Circulating human monocytes do not contain PPARgamma, but PPARgamma was induced rapidly (<4 h) in monocytes upon ligation of surface ICAM-3, but not P-selectin glycoprotein-1 even though both interactions prime cytokine secretion. Cyclooxygenase-2 induction by oxidized phospholipids only occurred in monocytes containing PPARgamma. Thus PPARgamma was induced rapidly in primary monocytes by appropriate outside-in signaling, sensitizing them to previously undetectable agonists in oxidized LDL. Cyclooxygenase-2 and PGE(2) secretion are induced, not inhibited, by selective PPARgamma agonists that include oxidatively fragmented phospholipids in oxidized LDL.[1]References
- Cyclooxygenase-2 is induced in monocytes by peroxisome proliferator activated receptor gamma and oxidized alkyl phospholipids from oxidized low density lipoprotein. Pontsler, A.V., St Hilaire, A., Marathe, G.K., Zimmerman, G.A., McIntyre, T.M. J. Biol. Chem. (2002) [Pubmed]
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