Role of TLR-4 in liver macrophage and endothelial cell responsiveness during acute endotoxemia
Role of TLR-4 in liver macrophage and endothelial cell responsiveness during acute endotoxemia
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DOI：
10.1016/j.yexmp.2007.08.015
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发表时间：
2007-12-01
影响因子：
3.6
通讯作者：
Laskin, Debra L.
中科院分区：
文献类型：
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作者：
Chen, Li C.;Gordon, Ronald E.;Laskin, Debra L.
肝巨噬细胞和血管内皮细胞与内毒素(ETX)引起的肝毒性有关。在这些研究中，我们分析了Toll样受体4(TLR-4)在这些细胞对急性内毒素血症反应中的作用。ETX(3 mg/kg，ip)对正常C3H/HeOuJ小鼠的治疗作用导致肝脏中活化的巨噬细胞数量增加。这与细胞的形态改变和快速(在3h内)诱导一氧化氮合酶-2、环氧合酶-2、微粒体PGE合成酶-1、白介素I-β和肿瘤坏死因子α基因的表达有关。在内皮细胞中，急性内毒素血症导致这些基因和5-脂氧合酶表达增加。相反，C3H/HeJ TLR-4突变小鼠的肝窦细胞对ETX的反应相对较弱，而对ETX处理的C3H/HeJ小鼠则无明显反应，导致肝窦细胞中转录因子AP-1和核因子-kappaB的激活，这种激活在3it内就很明显。而在巨噬细胞中，转录因子的激活是短暂的，而在内皮细胞中，转录因子的激活持续了24小时。在用ETX治疗的C3H/HeOuJ小鼠中，巨噬细胞和内皮细胞中也有p38 MAP激酶的激活，巨噬细胞中的JNK激酶也有明显的激活。相反，在巨噬细胞中发现蛋白激酶B(AKT)减少。在C3H/HeJ小鼠中，ETX还能激活巨噬细胞中的p38 MAP，而对JNK、P44/42 MAP和AKT无明显影响。这些研究表明，肝脏巨噬细胞和内皮细胞对急性内毒素血症有很高的反应能力。此外，这种活动在很大程度上依赖于TLR-4。(C)2007 Elsevier Inc.保留所有权利。
Liver macrophages and endothelial cells have been implicated in hepatotoxicity induced by endotoxin (ETX). In these studies, we analyzed the role of toll-like receptor 4 (TLR-4) in the response of these cells to acute endotoxemia. Treatment of control C3H/HeOuJ mice with ETX (3 mg/kg, i.p.) resulted in increased numbers of activated macrophages in the liver. This was associated with morphological changes in the cells and a rapid (within 3 h) induction of nitric oxide synthase-2, cyclooxygenase-2, microsomal PGE synthase-1, interleukin-I beta and tumor necrosis factor alpha gene expression. In endothelial cells, acute endotoxemia led to increased expression of these genes, as well as 5-lipoxygenase. In contrast, liver sinusoidal cells from C3H/HeJ TLR-4 mutant mice were relatively unresponsive to ETX Treatment of C3H/HeOuJ, but not C3H/HeJ mice with ETX, resulted in activation of transcription factors AP-1 and NF-kappa B in liver sinusoidal cells, which was evident within 3 It. Whereas in macrophages, transcription factor activation was transient, in endothelial cells, it persisted for 24 h. In C3H/HeOuJ mice treated with ETX, activation of p38 MAP kinase was also evident in macrophages and endothelial cells, and JNK kinase in macrophages. In contrast, reduced protein kinase B (AKT) was noted in macrophages. In C3H/HeJ mice, ETX administration also led to activation of p38 MAP kinase in macrophages with no effects on JNK, p44/42 MAP kinase or AKT. These studies demonstrate that liver macrophages and endothelial cells are highly responsive to acute endotoxemia. Moreover, this activity is largely dependent on TLR-4. (c) 2007 Elsevier Inc. All rights reserved.