title: Cyclooxygenase-2 is induced in monocytes by peroxisome proliferator activated receptor gamma and oxidized alkyl phospholipids from oxidized low density lipoprotein.
abstract: 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.
authors.affiliation: Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Aaron V
authors.initials: AV
authors.lastname: Pontsler
authors.forename: Andy
authors.initials: A
authors.lastname: St  Hilaire
authors.forename: Gopal K
authors.initials: GK
authors.lastname: Marathe
authors.forename: Guy A
authors.initials: GA
authors.lastname: Zimmerman
authors.forename: Thomas M
authors.initials: TM
authors.lastname: McIntyre
mesh_terms: D001483:Base Sequence; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D017931:DNA Primers; D015232:Dinoprostone / Q000096:biosynthesis; D004790:Enzyme Induction; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008565:Membrane Proteins; D009000:Monocytes / Q000201:enzymology*; D009578:Nitrobenzenes / Q000494:pharmacology; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D000077154:Rosiglitazone; D013449:Sulfonamides / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism / Q000502:physiology*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D017931:DNA Primers; D007527:Isoenzymes; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D009578:Nitrobenzenes; D010743:Phospholipids; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C099252:oxidized low density lipoprotein; D000077154:Rosiglitazone; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone