HMG-CoA reductase inhibitors induce COX-2 gene expression in murine macrophages: role of MAPK cascades and promoter elements for CREB and C/EBPbeta.
Except functioning as lipid-lowering agents, HMG-CoA inhibitors, statins, are good tools to clarify the signaling role of small G proteins. In this study, we found in murine RAW264.7 macrophages, statins within 1-30 microM stimulated COX-2 gene transcription and PGE(2) formation, displaying potencies as lovastatin > fluvastatin > atorvastatin >> pravastatin. Transfection experiments with COX-2 promoter construct showed the necessity of C/EBPbeta and CRE promoter sites, but not NF-kappaB promoter site. Effects of statins on the activation of COX-2 promoter, induction of COX-2 protein, and PGE(2) production were all prevented by mevalonate and prenylated metabolites, FPP and GGPP. Consistent with the effect of statins, manumycin A, farnesyltransferase inhibitor, and geranylgeranyltransferase inhibitor increased PGE(2) production and COX-2 induction. Likewise, toxin B, an inhibitor of Rho family members, caused a prominent COX-2 induction. Results also indicated that tyrosine kinase, ERK, and p38 MAPK play essential roles in statin action. Taken together, these results not only demonstrate a unique action of statins in the upregulation of COX-2 expression in macrophages, but also suggest a negative role controlled by small G proteins in COX-2 gene regulation. Removal of this negative control by impairing G protein prenylation with statins leads to MAPKs activation and promotes COX-2 gene expression through the activation at CRE and C/EBPbeta sites.
Chen
Jui-Ching
JC
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Huang
Kuo-Chin
KC
Wingerd
Byron
B
Wu
Wen-Tung
WT
Lin
Wan-Wan
WW
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D004742:Enhancer Elements, Genetic / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007527:Isoenzymes / Q000187:drug effects / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008264:Macrophages / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
D022782:CCAAT-Enhancer-Binding Protein-beta; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007527:Isoenzymes; D014157:Transcription Factors; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D019204:GTP-Binding Proteins; D015232:Dinoprostone