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

被引:87
作者
Matsumoto, M [1 ]
Einhaus, D [1 ]
Gold, ES [1 ]
Aderem, A [1 ]
机构
[1] Inst Syst Biol, Seattle, WA 98103 USA
关键词
D O I
10.4049/jimmunol.172.12.7377
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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-a 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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页码:7377 / 7384
页数:8
相关论文
共 42 条
[1]   Treatment of relapsing paralysis in experimental encephalomyelitis by targeting Th1 cells through atorvastatin [J].
Aktas, O ;
Waiczies, S ;
Smorodchenko, A ;
Dörr, J ;
Seeger, B ;
Prozorovski, T ;
Sallach, S ;
Endres, M ;
Brocke, S ;
Nitsch, R ;
Zipp, F .
JOURNAL OF EXPERIMENTAL MEDICINE, 2003, 197 (06) :725-733
[2]   Molecular cloning of mitogen-activated protein ERK kinase kinases (MEKK) 2 and 3 - Regulation of sequential phosphorylation pathways involving mitogen-activated protein kinase and c-Jun kinase [J].
Blank, JL ;
Gerwins, P ;
Elliott, EM ;
Sather, S ;
Johnson, GL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (10) :5361-5368
[3]   Regulation of an essential innate immune response by the p50 subunit of NF-κB [J].
Bohuslav, J ;
Kravchenko, VV ;
Parry, GCN ;
Erlich, JH ;
Gerondakis, S ;
Mackman, N ;
Ulevitch, RJ .
JOURNAL OF CLINICAL INVESTIGATION, 1998, 102 (09) :1645-1652
[4]   Cell-permeable peptide inhibitors of JNK novel blockers of β-cell death [J].
Bonny, C ;
Oberson, A ;
Negri, S ;
Sauser, C ;
Schorderet, DF .
DIABETES, 2001, 50 (01) :77-82
[5]   The induction of cyclooxygenase-2 mRNA in macrophages is biphasic and requires both CCAAT enhancer-binding protein β (C/EBPβ) and C/EBPδ transcription factors [J].
Caivano, M ;
Gorgoni, B ;
Cohen, P ;
Poli, V .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (52) :48693-48701
[6]   Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome [J].
Drenth, JPH ;
Cuisset, L ;
Grateau, G ;
Vasseur, C ;
van de Velde-Visser, SD ;
de Jong, JGN ;
Beckmann, JS ;
van der Meer, JWM ;
Delpech, M .
NATURE GENETICS, 1999, 22 (02) :178-181
[7]   Collaborative induction of inflammatory responses by dectin-1 and toll-like receptor 2 [J].
Gantner, BN ;
Simmons, RM ;
Canavera, SJ ;
Akira, S ;
Underhill, DM .
JOURNAL OF EXPERIMENTAL MEDICINE, 2003, 197 (09) :1107-1117
[8]   REGULATION OF THE MEVALONATE PATHWAY [J].
GOLDSTEIN, JL ;
BROWN, MS .
NATURE, 1990, 343 (6257) :425-430
[9]   Synergistic regulation of the human interleukin-12 p40 promoter by NFκB and Ets transcription factors in Epstein-Barr virus-transformed B cells and macrophages [J].
Gri, G ;
Savio, D ;
Trinchieri, G ;
Ma, XJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (11) :6431-6438
[10]  
HOFFMANN GF, 1993, PEDIATRICS, V91, P915