Bile Acids Induce Inflammatory Genes in Hepatocytes A Novel Mechanism of Inflammation during Obstructive Cholestasis
Bile Acids Induce Inflammatory Genes in Hepatocytes A Novel Mechanism of Inflammation during Obstructive Cholestasis
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DOI：
10.1016/j.ajpath.2010.11.026
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发表时间：
2011-01-01
影响因子：
6
通讯作者：
Copple, Bryan L.
中科院分区：
文献类型：
--
作者：
Allen, Katryn;Jaeschke, Hartmut;Copple, Bryan L.
炎症导致胆汁淤积期间的肝损伤。然而，胆汁淤积引发肝脏炎症反应的机制尚不清楚。本研究探讨了两个假设。首先，Toll样受体4（TLR 4）的激活，无论是由细菌脂多糖或由死亡肝细胞释放的损伤相关分子模式分子，触发炎症反应。第二，胆汁酸作为炎症因子，直接激活肝细胞中刺激促炎介质产生的信号通路。胆管结扎后，脂多糖耐药C3 H/HeJ小鼠的肝脏炎症没有受到影响，表明Toll样受体4不需要启动炎症。用胆汁酸处理肝细胞不会直接引起细胞毒性，但会增加许多促炎介质的表达，包括细胞因子、趋化因子、粘附分子和其他影响免疫细胞水平和功能的蛋白质。肝细胞和胆管结扎后肝脏中这些基因的上调需要早期生长反应因子-1，而不是法尼醇X受体。此外，早期生长反应因子-1在胆汁淤积患者的肝脏中上调，并与炎症介质水平相关。这些数据表明，Toll样受体4是不需要在胆汁淤积急性炎症的启动。相反，胆汁酸直接激活肝细胞中的信号网络，促进胆汁淤积期间的肝脏炎症。(Am J Pathol 2011，178：175-186 DOI：10.1016/j.ajpath.2010.11.026）
Inflammation contributes to liver injury during cholestasis. The mechanism by which cholestasis initiates an inflammatory response in the liver, however, is not known. Two hypotheses were investigated in the present studies. First, activation of Toll-like receptor 4 (TLR4), either by bacterial lipopolysaccharide or by damage-associated molecular pattern molecules released from dead hepatocytes, triggers an inflammatory response. Second, bile acids act as inflammagens, and directly activate signaling pathways in hepatocytes that stimulate production of proinflammatory mediators. Liver inflammation was not affected in lipopolysaccharide-resistant C3H/HeJ mice after bile duct ligation, indicating that Toll-like receptor 4 is not required for initiation of inflammation. Treatment of hepatocytes with bile acids did not directly cause cell toxicity but increased the expression of numerous proinflammatory mediators, including cytokines, chemokines, adhesion molecules, and other proteins that influence immune cell levels and function. Upregulation of several of these genes in hepatocytes and in the liver after bile duct ligation required early growth response factor-1, but not farnesoid X receptor. In addition, early growth response factor-1 was up-regulated in the livers of patients with cholestasis and correlated with levels of inflammatory mediators. These data demonstrate that Toll-like receptor 4 is not required for the initiation of acute inflammation during cholestasis. In contrast, bile acids directly activate a signaling network in hepatocytes that promotes hepatic inflammation during cholestasis. (Am J Pathol 2011, 178: 175-186 DOI: 10.1016/j.ajpath.2010.11.026)