Involvement of a pertussis toxin-sensitive G-protein-coupled phospholipase A2 in lipopolysaccharide-stimulated prostaglandin E2 synthesis in cultured rat mesangial cells.
E. coli lipopolysaccharide (LPS) stimulated a dose- and time-dependent release of prostaglandin E2 (PGE2) in cultured rat glomerular mesangial cells. Pertussis toxin, an inhibitor of several GTP-binding proteins (G proteins), blocked nearly 80% of the LPS-stimulated PGE2 formation, while having virtually no effect on calcium ionophore-stimulated PGE2 production. We tested the possibility that a G protein-coupled activation of phospholipase A2 mediated the LPS-stimulated PGE2 production. Evidence for LPS activation of phospholipase A2 included a time-dependent LPS-induced generation of [32P]lysophosphatidylcholine and the inhibitory effects of a phospholipase A2 inhibitor, mepacrine, on LPS-induced PGE2 formation. Possible roles for phospholipase C-dependent activation of PGE2 synthesis by LPS seemed unlikely, as LPS did not elevate the cytosolic free calcium concentration or augment the appearance of water-soluble inositol phosphates. We conclude that LPS-induced PGE2 synthesis in rat glomerular mesangial cells is mediated through a G-protein-coupled phospholipase A2 activation. The activation of phospholipase A2 releases arachidonic acid and stimulates PGE2 synthesis preferentially, thereby improving glomerular hemodynamic events in endotoxemia.
D000818:Animals; D002478:Cells, Cultured; D015232:Dinoprostone / Q000096:biosynthesis*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D037342:Pertussis Toxin; D010740:Phospholipases / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D051381:Rats; D010738:Type C Phospholipases / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D008070:Lipopolysaccharides; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin; D010740:Phospholipases; D010741:Phospholipases A; D054467:Phospholipases A2; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D015232:Dinoprostone