Regulation of constitutive and microbial pathogen-induced human macrophage migration inhibitory factor (MIF) gene expression

被引:53
作者
Roger, Thierry [1 ,2 ]
Ding, Xavier [1 ,2 ]
Chanson, Anne-Laure [1 ,2 ]
Renner, Pascal [1 ,2 ]
Calandra, Thierry [1 ,2 ]
机构
[1] CHU Vaudois, Dept Med, Infect Dis Serv, CH-1011 Lausanne, Switzerland
[2] Univ Lausanne, Lausanne, Switzerland
关键词
cytokines; inflammation; innate immunity; macrophage; migration inhibitory factor; monocytes/macrophages;
D O I
10.1002/eji.200737357
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 cytokine macrophage migration inhibitory factor (MIF) is an important regulator of innate immunity, inflammation and oncogenesis. However, four decades after its identification, the molecular mechanism(s) regulating the expression of the MIF gene remain largely unknown. Analyses of human monocytic (THP-1), epithelial (HeLa and A549) and keratinocytic (HaCat) cells transfected with wild-type, truncated and mutated MIF promoter reporter constructs, and electrophoretic mobility shift assay, chromatin immunoprecipitation, and siRNA inhibition indicated that the transcription factors specificity protein (Sp)1 and cAMP response element-binding protein (CREB) are critical positive regulators of constitutive human MIF gene expression. Albeit located in a cytosine guanine dinucleotide island, the MIF gene was found to be hypomethylated, an observation consistent with high baseline transcriptional activity. Moreover, stimulation of THP-1 cells and of peripheral blood mononuclear cells with microbial products up-regulated phosphorylated Sp1 nuclear content, Sp1 DNA-binding activity, MIF promoter activity and MIF mRNA levels in a MEK1/2-, Sp1-dependent manner. Taken together with previous observations of an important role for MIF in pro-inflammatory macrophage responses, these present findings suggest a key role for Spl and CREB in transcriptional regulation of MIF gene expression and MIF-dependent host antimicrobial innate immune defense.
引用
收藏
页码:3509 / 3521
页数:13
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