HMG-CoA reductase inhibitors induce COX-2 gene expression in murine macrophages: role of MAPK cascades and promoter elements for CREB and C/EBPβ

• Published in: Experimental cell research Vol. 301; no. 2; pp. 305 - 319
• Main Authors: Chen, Jui-Ching, Huang, Kuo-Chin, Wingerd, Byron, Wu, Wen-Tung, Lin, Wan-Wan
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 10.12.2004
• Subjects: Cyclooxygenase-2; G protein prenylation; Macrophages; MAPKs; Statins; G protein prenylation; Cyclooxygenase-2; Macrophages; Statins; MAPKs
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2004.05.039

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 μM 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/EBPβ and CRE promoter sites, but not NF-κB 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/EBPβ sites.