Regulation of Toll-like receptor 4 expression in the lung following hemorrhagic shock and lipopolysaccharide
Regulation of Toll-like receptor 4 expression in the lung following hemorrhagic shock and lipopolysaccharide
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DOI：
10.4049/jimmunol.168.10.5252
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发表时间：
2002-05-15
影响因子：
4.4
通讯作者：
Rotstein, OD
中科院分区：
文献类型：
--
作者：
Fan, J;Kapus, A;Rotstein, OD
Toll样受体4（TLR 4）最近被证明是LPS的主要上游传感器。本研究利用啮齿类动物失血性休克复苏后肺损伤模型，在体内外研究TLR 4基因和蛋白表达的调控。单独的气管内LPS诱导全肺TLR 4 mRNA的快速减少，这种作用也在恢复的肺泡巨噬细胞中观察到。这种效应似乎是由于TLR 4 mRNA稳定性降低了约69%。相比之下，虽然休克/复苏单独对TLR 4 mRNA水平没有影响，但它显着改变了对LPS的反应。具体而言，预先休克阻止LPS诱导的TLR 4 mRNA水平的降低。这种逆转的解释是，与单独的LPS相比，先前复苏的休克既能防止LPS对TLR 4 mRNA的不稳定，又能增加LPS刺激的TLR 4基因转录。与休克/复苏相关的氧化应激似乎有助于调节TLR 4 mRNA，因为用抗氧化剂N-乙酰半胱氨酸补充复苏液逆转了LPS后休克/复苏保护TLR 4 mRNA水平的能力。整个肺中的TLR 4蛋白水平反映了TLR 4 mRNA的变化。总的来说，这些数据表明，TLR 4的表达水平控制转录以及转录后通过改变mRNA的稳定性和先行休克/复苏，一种形式的全球缺血/再灌注，可能会影响该基因的调节。
The Toll-like receptor 4 (TLR4) has recently been shown to function as the major upstream sensor for LPS. In this study, a rodent model of lung injury following resuscitated hemorrhagic shock was used to examine the regulation of TLR4 gene and protein expression in vivo and in vitro. Intratracheal LPS alone induced a rapid reduction in whole lung TLR4 mRNA, an effect which is also observed in recovered alveolar macrophages. This effect appeared to be due to a lowering of TLR4 mRNA stability by similar to69%. By contrast, while shock/resuscitation alone had no effect on TLR4 mRNA levels, it markedly altered the response to LPS. Specifically, antecedent shock prevented the LPS-induced reduction in TLR4 mRNA levels. This reversal was explained by the ability of prior resuscitated shock both to prevent the destabilization of TLR4 mRNA by LPS and also to augment LPS-stimulated TLR4 gene transcription compared with LPS alone. Oxidant stress related to shock/resuscitation appeared to contribute to the regulation of TLR4 mRNA, because supplementation of the resuscitation fluid with the antioxidant N-acetyleysteine reversed the ability of shock/resuscitation to preserve TLR4 mRNA levels following LPS. TLR4 protein levels in whole lung mirrored the changes seen for TLR4 mRNA. Considered in aggregate, these data suggest that levels of tlr4 expression are controlled both transcriptionally as well as posttranscriptionally through altered mRNA stability and that antecedent shock/resuscitation, a form of global ischemia/reperfusion, might influence regulation of this gene.