Interleukin-1β inhibits CAR-induced expression of hepatic genes involved in drug and bilirubin clearance
Interleukin-1β inhibits CAR-induced expression of hepatic genes involved in drug and bilirubin clearance
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DOI：
10.1002/hep.20387
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发表时间：
2004-10-01
期刊：
影响因子：
13.5
通讯作者：
Pascussi, JM
中科院分区：
文献类型：
--
作者：
Assenat, E;Gerbal-Chaloin, S;Pascussi, JM
在炎症反应期间，经常观察到肝内胆汁淤积和药物代谢降低。在肝脏水平，孤儿核组成型雄甾受体（CAR） （NR1I3）控制I期（细胞色素P450 [CYP] 2B和CYP3A）、II期（UGT1A1）和转运体（SLC21A6, MRP2）基因，这些基因参与药物代谢和胆红素清除，以应对外源药物如苯巴比妥或内源性药物如胆红素。我们通过促炎细胞因子白细胞介素1 β (il -1 β)和脂多糖（lps）在人肝细胞中研究了糖皮质激素应答基因CAR的负调控。我们发现il -1 β降低了CAR的表达，并降低了苯巴比多或胆红素介导的CYP2B6、CYP2C9、CYP3A4、UGT1A1、GSTA1、GSTA2和SLC21A6信使RNA的诱导。这是通过核因子kappaB (NF-kappaB) p65激活发生的，它干扰了我们最近在CAR启动子中发现的远端糖皮质激素反应元件的增强子功能。我们证明：(1)lps、il -1 β或p65RelA的过表达抑制糖皮质激素受体（GR）介导的CAR转激活；(2)这些抑制作用可以被吡咯烷二硫代氨基甲酸酯（NF-kappaB激活抑制剂）或过表达SRIkBalpha （NF-kappaB抑制因子）阻断；(3) GR激动剂地塞米松在近端CAR启动子区域诱导组蛋白H4乙酰化，而lps和il -1 β抑制这种乙酰化，这是通过染色质免疫沉淀试验评估的。总之，GR/NF-kappaB相互作用通过染色质重塑影响CAR基因转录，并为长期观察到的炎症和脓毒症抑制药物代谢同时诱导肝内胆汁淤积或高胆红素血症提供了机制解释。
During the inflammatory response, intrahepatic cholestasis and decreased drug metabolism are frequently observed. At the hepatic level, the orphan nuclear constitutive androstane receptor (CAR) (NR1I3) controls phase I (cytochrome P450 [CYP] 2B and CYP3A), phase II (UGT1A1), and transporter (SLC21A6, MRP2) genes involved in drug metabolism and bilirubin clearance in response to xenobiotics such as phenobarbital or endobiotics such as bilirubin. We investigated the negative regulation of CAR, a glucocorticoid-responsive gene, via proinflammatory cytokine interleukin 1beta (IL-1beta) and lipopolysaccharides (LPSs) in human hepatocytes. We show that IL-1beta decreases CAR expression and decreases phenobarbital- or bilirubin-mediated induction of CYP2B6, CYP2C9, CYP3A4, UGT1A1, GSTA1, GSTA2, and SLC21A6 messenger RNA. This occurs via nuclear factor kappaB (NF-kappaB) p65 activation, which interferes with the enhancer function of the distal glucocorticoid response element that we have identified recently in the CAR promoter. We demonstrate that: (1) LPSs, IL-1beta, or overexpression of p65RelA inhibit glucocorticoid receptor (GR)-mediated CAR transactivation; (2) these suppressive effects can be blocked both by pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB activation, or by overexpression of SRIkBalpha, a NF-kappaB repressor; and (3) the GR agonist dexamethasone induces histone H4 acetylation at the proximal CAR promoter region, whereas LPSs and IL-1beta inhibit this acetylation as assessed via chromatin immunoprecipitation assay. In conclusion, GR/NF-kappaB interaction affects CAR gene transcription through chromatin remodeling and provide a mechanistic explanation for the long-standing observation that inflammation and sepsis inhibit drug metabolism while inducing intrahepatic cholestasis or hyperbilirubinemia.