Induction of cyclo‐oxygenase‐2 expression by methyl arachidonyl fluorophosphonate in murine J774 macrophages: roles of protein kinase C, ERKs and p38 MAPK

• Published in: British journal of pharmacology 1999-03, Vol.126 (6), p.1419-1425
• Main Authors: Lin, Wan‐W, Chen, Bing‐C
• Format: Article
• Language: English
• Subjects: Animals; Arachidonic Acids - pharmacology; Biological and medical sciences; Calcium-Calmodulin-Dependent Protein Kinases - physiology; COX‐2 expression; Cyclooxygenase 1; Dinoprost - secretion; Dose-Response Relationship, Drug; Enzyme Activation - drug effects; Enzyme Induction - drug effects; Enzyme Inhibitors - pharmacology; ERK; Fundamental and applied biological sciences. Psychology; Gene Expression - drug effects; Inflammation; Isoenzymes - genetics; J774 macrophage; Macrophages - cytology; Macrophages - drug effects; Macrophages - enzymology; MAFP; Membrane Proteins; Mice; Mitogen-Activated Protein Kinases; Molecular and cellular biology; Organophosphonates; p38 MAPK; p38 Mitogen-Activated Protein Kinases; Phospholipases A - antagonists & inhibitors; Phospholipases A2; PKC; Prostaglandin-Endoperoxide Synthases - genetics; Protein Kinase C - physiology; RNA, Messenger - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; Time Factors
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0702436

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. The murine macrophage J774 released a large amount of prostaglandin E2 (PGE2) by MAFP (1–30 μM), 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. 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). Consistent with these results, MAFP caused membrane translocation of PKCβI and βII isoforms and activated extracellular signal‐regulated kinase (ERK) and p38 MAPK. In accordance with these effects of MAFP, PKC activator phorbol 12‐myristate 13‐acetate (PMA) increased PGE2 release and caused activation of PKCβ, ERKs and p38 MAPK. 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. British Journal of Pharmacology (1999) 126, 1419–1425; doi:10.1038/sj.bjp.0702436