Modulation of cyclooxygenase-2 expression by phosphatidylcholine specific phospholipase C and D in macrophages stimulated with lipopolysaccharide.
Lipopolysaccharide (LPS) enhances the expression of cyclooxygenase 2 (COX-2) in macrophages, and stimulates production of prostaglandins that cause endothelial dysfunction in septic shock. In an effort to identify strategies for reducing LPS-inducible expression of COX-2, inhibitors of the phospholipases involved in LPS dependent over-expression of COX-2 were studied. LPS enhances expression of COX-2 mRNA and protein by activating sequentially phosphatidylcholine-specific phospholipase C (PC-PLC), protein kinase C (PKC) and phosphatidylcholine-specific phospholipase D (PC-PLD). This stimulates production of phosphatidic acid (PA), which increases expression of COX-2 mRNA and protein. Inhibition of PC-PLC by D609 (tricyclodecanoyl xanthogenate), and of PC-PLD activity by 1-butanol, reduced LPS-dependent over-production of PA and suppressed the increase of COX-2 mRNA and protein. Activation of PKC, normally seen in LPS-treated cells, was mimicked with phorbol myristic acid (PMA), and this also increased PA production and enhanced COX-2 expression. Propranolol inhibition of phosphatidic acid phosphohydrolase (PPH) increased PA accumulation and enhanced LPS-dependent COX-2 protein synthesis. These results suggest that inhibitors of PC-PLC, PKC and PC-PLD, or activators of PPH could be useful in the management of LPS-induced overproduction of prostaglandins and of vascular dysfunction in septic shock.
Lee
Sung-Chang
SC
Nitric Oxide Radical Toxicology Research Center and Department of Pharmacology and Toxicology, College of Medicine, Inha University, Incheon 402-751, Korea.
Han
Joong-Soo
JS
Seo
Jeong-Kee
JK
Cha
Young-Nam
YN
D020001:1-Butanol / Q000494:pharmacology; D000818:Animals; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009636:Norbornanes; D010712:Phosphatidic Acids / Q000494:pharmacology; D010739:Phospholipase D / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology; D010738:Type C Phospholipases / Q000494:pharmacology*
D001952:Bridged-Ring Compounds; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008070:Lipopolysaccharides; D009636:Norbornanes; D010712:Phosphatidic Acids; D012333:RNA, Messenger; D013859:Thiocarbamates; D013871:Thiones; C046498:tricyclodecane-9-yl-xanthogenate; D020001:1-Butanol; D011433:Propranolol; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C; D010739:Phospholipase D