Simvastatin augments lipopolysaccharide-induced proinflammatory responses in macrophages by differential regulation of the c-Fos and c-Jun transcription factors

TitleSimvastatin augments lipopolysaccharide-induced proinflammatory responses in macrophages by differential regulation of the c-Fos and c-Jun transcription factors
Publication TypeJournal Article
Year of Publication2004
AuthorsMatsumoto M, Einhaus D, Gold ES, Aderem A
JournalJ Immunol
Volume172
Pagination7377-84
Date PublishedJun 15
PMID15187114
KeywordsAdjuvants, Immunologic/pharmacology, Animals, CCAAT-Enhancer-Binding Proteins/physiology, Drug Synergism, Female, Gene Expression Regulation/drug effects/*immunology, Inflammation/*chemically induced, Interleukin-12 Subunit p40, Interleukin-12/biosynthesis, Lipopolysaccharides/*pharmacology, Macrophages/drug effects/*immunology, Mice, Mice, Inbred C57BL, Promoter Regions, Genetic/drug effects, Protein Subunits/biosynthesis, Proto-Oncogene Proteins c-fos/genetics/physiology, Proto-Oncogene Proteins c-jun/genetics/physiology, Simvastatin/*pharmacology, Transcription Factor AP-1/physiology, Transcription Factors/*genetics/physiology
AbstractThe 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.

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