Hypoxia diminishes toll-like receptor 4 expression through reactive oxygen species generated by mitochondria in endothelial cells
Hypoxia diminishes toll-like receptor 4 expression through reactive oxygen species generated by mitochondria in endothelial cells
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DOI：
10.4049/jimmunol.169.4.2069
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发表时间：
2002-08-15
影响因子：
4.4
通讯作者：
Kondo, T
中科院分区：
文献类型：
--
作者：
Ishida, I;Kubo, H;Kondo, T
缺氧和炎症往往同时发生，由于阻止充分的气体交换。了解缺氧对炎症反应的影响很重要，因为缺氧直接调节许多基因的表达，包括那些调节炎症的基因，并在调节炎症反应的消退中起作用。LPS是细胞损伤和炎症的主要介质，其通过Toll样受体4（TLR 4）诱导其作用。本研究的目的是评估缺氧对TLR 4表达的影响。缺氧降低内皮细胞TLR 4表达。此外，LPS诱导的ICAM-1的上调被缺氧降低。由于线粒体产生的活性氧（ROS）是缺氧诱导的信号分子之一，因此评估了ROS在缺氧诱导的TLR 4下调中的作用。我们的数据表明，缺氧增加ROS的产生和缺氧诱导的TLR 4下调抑制myxothiazol，线粒体位点III电子传递抑制剂。缺氧也抑制AP-1易位。由于TLR 4启动子具有AP-1结合位点，因此缺氧诱导的TLR 4下调可能是由于ROS介导的AP-1结合活性降低。我们的结论是，缺氧降低TLR 4在内皮细胞的表达，这种变化是由线粒体ROS介导的AP-1的转录活性衰减。
Hypoxia and inflammation often occur simultaneously due to prevention of adequate gas exchange. Understanding the influence of hypoxia on the inflammatory response is important because hypoxia directly regulates expression of many genes, including those regulating inflammation, and plays a role in modulating the resolution of an inflammatory response. LPS is a major mediator of cellular injury and inflammation that induces its effects through Toll-like receptor 4 (TLR4). The aim of this study was to evaluate the effect of hypoxia on TLR4 expression. Hypoxia decreased TLR4 expression on cultured endothelial cells. Furthermore, LPS-induced ICAM-1 up-regulation was decreased by hypoxia. Because reactive oxygen species (ROS) generated from mitochondria are one of the signaling molecules induced by hypoxia, the role of ROS in hypoxia-induced TLR4 down-regulation was evaluated. Our data showed that hypoxia increased ROS generation and that hypoxia-induced TLR4 down-regulation was inhibited by myxothiazol, a mitochondrial site III electron transport inhibitor. Hypoxia also inhibited AP-1 translocation. Since the TLR4 promoter has a binding site for AP-1, hypoxia-induced TLR4 down-regulation may be due to an ROS-mediated decrease in AP-1-binding activity. We conclude that hypoxia decreases TLR4 expression in endothelial cells and that this change is mediated by mitochondrial ROS leading to attenuation of AP-1 transcriptional activity.