The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88.
The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88.
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DOI：
10.1002/hep.22470
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发表时间：
2008-10
期刊：
影响因子：
--
通讯作者：
Szabo G
中科院分区：
文献类型：
--
作者：
Hritz I;Mandrekar P;Velayudham A;Catalano D;Dolganiuc A;Kodys K;Kurt-Jones E;Szabo G
识别内毒素的Toll样受体4（TLR 4）是酒精性肝病（ALD）中炎症的触发因子，其利用不同的衔接分子激活两种信号传导途径：常见的TLR衔接子、髓样分化因子88（MyD 88）或Toll/含白细胞介素免疫应答结构域的衔接子诱导干扰素（IFN）-β。MyD 88通路诱导促炎细胞因子活化，这是ALD的关键介质。在这里，我们评估了MyD 88在野生型、TLR 2缺陷型、TLR 4缺陷型或MyD 88缺陷型（敲除[KO]）小鼠中给予Lieber-De-Carli饮食（4.5%体积/体积乙醇）或等热量液体对照饮食5周后在酒精诱导的肝损伤中的作用。酒精喂养导致血清丙氨酸氨基转移酶水平、肝脏脂肪变性和甘油三酯水平的显著增加，表明WT、TLR 2-KO和MyD 88-KO小鼠的肝损伤，但TLR 4-KO小鼠没有。与对照组相比，在酒精喂养的WT、TLR 2-KO或MyD 88-KO小鼠的肝脏中，炎症介质（肿瘤坏死因子-α和白细胞介素-6）和TLR 4辅助受体（CD 14和MD 2）的表达显著升高，但在TLR 4-KO小鼠中则没有。由细胞色素P450和烟酰胺腺嘌呤二核苷酸磷酸复合物产生的活性氧自由基有助于酒精性肝损伤。酒精喂养诱导的细胞色素P450和烟酰胺腺嘌呤二核苷酸磷酸复合物的表达和激活被TLR 4缺乏阻止，但不是MyD 88缺乏。干扰素调节因子3（IRF 3）（一种MyD 88非依赖性信号分子）的肝脏表达不受WT小鼠或任何KO小鼠整个肝脏长期酒精处理的影响。然而，在酒精喂养的WT小鼠的Kupffer细胞中发现了IRF 3诱导基因IRF 7的诱导。酒精喂养也诱导核因子-κB激活的TLR 4依赖性MyD 88非依赖性的方式。虽然TLR 4缺乏具有保护作用，但MyD 88缺乏未能预防酒精诱导的肝损伤和炎症。这些结果表明，常见的TLR衔接子MyD 88在ALD中TLR 4介导的肝损伤中被抑制。
The Toll-like receptor 4 (TLR4) that recognizes endotoxin, a trigger of inflammation in alcoholic liver disease (ALD), activates two signaling pathways utilizing different adapter molecules: the common TLR adapter, myeloid differentiation factor 88 (MyD88), or Toll/interleukin immune-response–domain-containing adaptor inducing interferon (IFN)-β. The MyD88 pathway induces proinflammatory cytokine activation, a critical mediator of ALD. Here we evaluated the role of MyD88 in alcohol-induced liver injury in wild-type, TLR2-deficient, TLR4-deficient, or MyD88-deficient (knockout [KO]) mice after administration of the Lieber-De-Carli diet (4.5% volume/volume ethanol) or an isocaloric liquid control diet for 5 weeks. Alcohol feeding resulted in a significant increase in serum alanine aminotransferase levels, liver steatosis and triglyceride levels suggesting liver damage in WT, TLR2-KO, and MyD88-KO but not in TLR4-KO mice. Expression of inflammatory mediators (tumor necrosis factor–α and interleukin-6) and TLR4 coreceptors (CD14 and MD2) was significantly higher in livers of alcohol-fed WT, TLR2-KO, or MyD88-KO, but not in TLR4-KO mice, compared to controls. Reactive oxygen radicals produced by cytochrome P450 and the nicotinamide adenine dinucleotide phosphate complexes contribute to alcoholic liver damage. Alcohol feeding–induced expression and activation of cytochrome P450 and the nicotinamide adenine dinucleotide phosphate complex were prevented by TLR4-deficiency but not by MyD88-deficiency. Liver expression of interferon regulatory factor 3 (IRF3), a MyD88-independent signaling molecule, was not affected by chronic alcohol treatment in whole livers of WT mice or in any of the KO mice. However, the induction of IRF7, an IRF3-inducible gene, was found in Kupffer cells of alcohol-fed WT mice. Alcohol feeding also induced nuclear factor–κB activation in a TLR4-dependent MyD88-independent manner. While TLR4 deficiency was protective, MyD88 deficiency failed to prevent alcohol-induced liver damage and inflammation. These results suggest that the common TLR adapter, MyD88, is dispensable in TLR4-mediated liver injury in ALD.
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影响因子：
29.4
作者：
De Minicis, Samuele;Bataller, Ramon;Brenner, David A.
通讯作者：
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影响因子：
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作者：
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DOI：
10.1097/01.alc.0000189280.19073.28
发表时间：
2005-11-01
影响因子：
3.2
作者：
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通讯作者：
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影响因子：
29.4
作者：
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通讯作者：
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影响因子：
29.4
作者：
McKim, SE;Gäbele, E;Arteel, GE
通讯作者：
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