Kim Nam Deuk, Moon Jeon-Ok, Slitt Angela L, Copple Bryan L
Department of Pharmacology, Toxicology, and Experimental Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Toxicol Sci. 2006 Apr;90(2):586-95. doi: 10.1093/toxsci/kfj111. Epub 2006 Jan 19.
Hepatocyte injury during cholestasis depends in part on the release of proinflammatory mediators that cause neutrophils to accumulate in the liver and become activated to damage hepatocytes. The mechanism by which cholestasis stimulates production of proinflammatory mediators in the liver is not completely understood. The studies presented here tested the hypothesis that the transcription factor early growth response factor-1 (Egr-1) is required for inflammation to occur in the liver during cholestasis. The results of these studies show that Egr-1 was rapidly upregulated, primarily in hepatocytes, in mice subjected to bile duct ligation, an animal model of cholestasis. To determine whether Egr-1 was required for inflammation and hepatocyte injury during cholestasis, bile duct ligation was performed in wild-type and Egr-1 knockout mice. Hepatocyte injury, neutrophil accumulation, and upregulation of macrophage inflammatory protein-2 (MIP-2) and intercellular adhesion molecule-1 (ICAM-1) in the liver were significantly reduced in Egr-1 knockouts. By contrast, levels of tumor necrosis factor-alpha (TNF-alpha) and collagen (i.e., a biomarker of liver fibrosis) were not different between wild-types and Egr-1 knockouts subjected to bile duct ligation. Because hepatocytes are exposed to elevated concentrations of bile acids during cholestasis, it was determined that bile acids upregulate Egr-1 in primary mouse hepatocytes. Deoxycholic acid dose-dependently increased Egr-1 protein in hepatocytes. Results from these studies suggest a scenario in which elevated concentrations of bile acids during cholestasis increase expression of Egr-1 in hepatocytes. Egr-1 then upregulates proinflammatory mediators that cause neutrophils to accumulate in the liver and become activated to damage hepatocytes.
胆汁淤积期间的肝细胞损伤部分取决于促炎介质的释放，这些介质会导致中性粒细胞在肝脏中积聚并被激活，从而损伤肝细胞。胆汁淤积刺激肝脏中促炎介质产生的机制尚未完全明确。本文所呈现的研究检验了这样一个假说，即转录因子早期生长反应因子-1（Egr-1）是胆汁淤积期间肝脏发生炎症所必需的。这些研究结果表明，在胆管结扎（一种胆汁淤积的动物模型）的小鼠中，Egr-1迅速上调，主要在肝细胞中上调。为了确定Egr-1是否是胆汁淤积期间炎症和肝细胞损伤所必需的，对野生型和Egr-1基因敲除小鼠进行了胆管结扎。在Egr-1基因敲除小鼠中，肝细胞损伤、中性粒细胞积聚以及肝脏中巨噬细胞炎性蛋白-2（MIP-2）和细胞间黏附分子-1（ICAM-1）的上调均显著减少。相比之下，胆管结扎的野生型和Egr-1基因敲除小鼠之间，肿瘤坏死因子-α（TNF-α）和胶原蛋白（即肝纤维化的生物标志物）水平没有差异。由于胆汁淤积期间肝细胞会暴露于升高浓度的胆汁酸中，因此确定胆汁酸可上调原代小鼠肝细胞中的Egr-1。脱氧胆酸可剂量依赖性地增加肝细胞中Egr-1蛋白的表达。这些研究结果提示了一种情况，即胆汁淤积期间升高的胆汁酸浓度会增加肝细胞中Egr-1的表达。然后，Egr-1上调促炎介质，导致中性粒细胞在肝脏中积聚并被激活，从而损伤肝细胞。
