title: Induction of cyclo-oxygenase-2 expression by methyl arachidonyl fluorophosphonate in murine J774 macrophages: roles of protein kinase C, ERKs and p38 MAPK.
abstract: 1. Methyl arachidonyl fluorophosphonate (MAFP), an inhibitor of phospholipase A2 (PLA2), has been widely used to assess the roles of PLA2 in various cell functions. Here, we report on a novel action of this compound at concentrations similar to those used for PLA2 inhibition. 2. The murine macrophage J774 released a large amount of prostaglandin E2 (PGE2) by MAFP (1-30 microM), which was abolished by indomethacin and NS-398 but not by valeryl salicylate, and results from increased cyclo-oxygenase-2 (COX-2) protein levels and gene expression. 3. This PGE2 release was blocked by inhibitors of tyrosine kinase (genistein), protein kinase C (PKC) (Ro 31-8220, Go 6976 or LY 379196), mitogen-activated protein kinase kinase (MEK) (PD 098059) or p38 mitogen-activated protein kinase (MAPK) (SB 203580). 4. Consistent with these results, MAFP caused membrane translocation of PKCbetaI and betaII isoforms and activated extracellular signal-regulated kinase (ERK) and p38 MAPK. 5. In accordance with these effects of MAFP, PKC activator phorbol 12-myristate 13-acetate (PMA) increased PGE2 release and caused activation of PKCbeta, ERKs and p38 MAPK. 6. This is the first report that the PLA2 inhibitor, MAFP, can induce COX-2 gene expression and PGE2 synthesis via the PKC-, ERK- and p38 MAPK-dependent pathways. Thus, the use of MAFP as a PLA2 inhibitor should be treated with caution.
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei. wwl@ha.mc.ntu.edu.tw
authors.forename: W W
authors.initials: WW
authors.lastname: Lin
authors.forename: B C
authors.initials: BC
authors.lastname: Chen
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D051545:Cyclooxygenase 1; D015237:Dinoprost / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D007527:Isoenzymes / Q000235:genetics*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D008565:Membrane Proteins; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D063065:Organophosphonates; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D011493:Protein Kinase C / Q000502:physiology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D001095:Arachidonic Acids; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D063065:Organophosphonates; D012333:RNA, Messenger; C104810:methyl arachidonylfluorophosphonate; D015237:Dinoprost; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D054467:Phospholipases A2