A nuclear receptor corepressor-dependent pathway mediates suppression of cytokine-induced C-reactive protein gene expression by liver X receptor

被引:57
作者
Blaschke, Florian
Takata, Yasunori
Caglayan, Evren
Collins, Alan
Tontonoz, Peter
Hsueh, Willa A.
Tangirala, Rajendra K. [1 ]
机构
[1] Univ Calif Los Angeles, David Geffen Sch Med, Div Endocrinol Diabet & Hypertens, Los Angeles, CA 90095 USA
[2] Ehime Univ, Grad Sch Med, Dept Mol & Med Genet, Matsuyama, Ehime 790, Japan
[3] Univ Calif Los Angeles, Howard Hughes Med Inst, Inst Mol Biol, Los Angeles, CA 90024 USA
[4] Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90024 USA
[5] Humboldt Univ, Charite, HELIOS Clin GmbH, Max Delbruck Ctr Mol Med,Dept Mol & Clin Cardiol, D-1086 Berlin, Germany
关键词
C-reactive protein; liver X receptor; nuclear receptor corepressor;
D O I
10.1161/01.RES.0000252878.34269.06
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
C-reactive protein (CRP), the prototypical human acute phase protein, is an independent risk predictor of future cardiovascular events, both in healthy individuals and in patients with known cardiovascular disease. In addition, previous studies indicate that CRP might have direct proatherogenic properties. Ligand activation of the liver X receptor (LXR), a member of the nuclear hormone receptor superfamily, inhibits inflammatory gene expression in macrophages and attenuates the development of atherosclerosis in various animal models. We demonstrate herein that 2 synthetic LXR ligands, T0901317 and GW3965, inhibit interleukin-1 beta/interleukin-6-induced CRP mRNA and protein expression in human hepatocytes. Knockdown of LXR alpha/beta by short interfering RNAs completely abolished the inhibitory effect of the LXR agonist T0901317 on cytokine-induced CRP gene transcription. Transient transfection experiments with 5'-deletion CRP promoter constructs identified a region from -125 to -256 relative to the initiation site that mediated the inhibitory effect of LXR ligands on CRP gene transcription. Depletion of the nuclear receptor corepressor by specific short interfering RNA increased cytokine-inducible CRP mRNA expression and promoter activity and reversed LXR ligand-mediated repression of CRP gene transcription. Chromatin immunoprecipitation assays indicated that nuclear receptor corepressor is present on the endogenous CRP promoter under basal conditions. Cytokine-induced clearance of nuclear receptor corepressor complexes was inhibited by LXR ligand treatment, maintaining the CRP gene in a repressed state. Finally, treatment of C57B16/J mice with LXR ligands attenuated lipopolysaccharide-induced mouse CRP and serum amyloid P component gene expression in the liver, whereas no effect was observed in LXR alpha beta knockout mice. Our observations identify a novel mechanism of inflammatory gene regulation by LXR ligands. Thus, inhibition of CRP expression by LXR agonists may provide a promising approach to impact initiation and progression of atherosclerosis.
引用
收藏
页码:E88 / E99
页数:12
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