Simvastatin augments lipopolysaccharide-induced proinflammatory responses in macrophages by differential regulation of the c-Fos and c-Jun transcription factors.
The 3-hydroxyl-3-methylglutaryl-coenzyme A reductase inhibitors, or statins, are a widely used class of drugs for cholesterol reduction. The reduction in mortality and morbidity in statin-treated patients is incompletely explained by their effects on cholesterol, and an anti-inflammatory role for the drug has been proposed. We report in this work that, unexpectedly, simvastatin enhances LPS-induced IL-12p40 production by murine macrophages, and that it does so by activating the IL-12p40 promoter. Mutational analysis and dominant-negative expression studies indicate that both C/EBP and AP-1 transcription factors have a crucial role in promoter activation. This occurs via a c-Fos- and c-Jun-based mechanism; we demonstrate that ectopic expression of c-Jun activates the IL-12p40 promoter, whereas expression of c-Fos inhibits IL-12p40 promoter activity. Simvastatin prevents LPS-induced c-Fos expression, thereby relieving the inhibitory effect of c-Fos on the IL-12p40 promoter. Concomitantly, simvastatin induces the phosphorylation of c-Jun by the c-Jun N-terminal kinase, resulting in c-Jun-dependent activation of the IL-12p40 promoter. This appears to be a general mechanism because simvastatin also augments LPS-dependent activation of the TNF-alpha promoter, perhaps because the TNF-alpha promoter has C/EBP and AP-1 binding sites in a similar configuration to the IL-12p40 promoter. The fact that simvastatin potently augments LPS-induced IL-12p40 and TNF-alpha production has implications for the treatment of bacterial infections in statin-treated patients.
Matsumoto
Makoto
M
Institute for Systems Biology, 1441 North 34th Street, Seattle, WA 98103-8904, USA.
Einhaus
Derek
D
Gold
Elizabeth S
ES
Aderem
Alan
A
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology; D004357:Drug Synergism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D007249:Inflammation / Q000139:chemically induced*; D018664:Interleukin-12 / Q000096:biosynthesis; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000187:drug effects; D021122:Protein Subunits / Q000096:biosynthesis; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000502:physiology; D019821:Simvastatin / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology
D000276:Adjuvants, Immunologic; D022762:CCAAT-Enhancer-Binding Proteins; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides; D021122:Protein Subunits; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D018664:Interleukin-12; D019821:Simvastatin