TLR4 signaling induces TLR2 expression in endothelial cells via neutrophil NADPH oxidase.
TLR4 signaling induces TLR2 expression in endothelial cells via neutrophil NADPH oxidase.
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DOI：
10.1172/jci18696
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发表时间：
2003-10
期刊：
影响因子：
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通讯作者：
Jie Fan;R. Frey;A. Malik
中科院分区：
文献类型：
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作者：
Jie Fan;R. Frey;A. Malik
多形核中性粒细胞（PMNs）与内皮细胞的相互作用可能有助于激活参与先天免疫的内皮细胞反应。我们探讨了中性粒细胞NADPH氧化酶在LPS-TLR 4信号诱导的内皮细胞Toll样受体2（TLR 2）上调机制中的新功能。我们发现LPS通过TLR 4和MyD 88依赖性信号转导诱导TLR 2上调。在血小板减少的小鼠中，LPS诱导的NF-κ B活化和TLR 2表达显著降低，并且这两种反应在从WT小鼠获得的PMN而不是从NADPH氧化酶gp 91 pho（-/-）小鼠获得的PMN饱足后恢复。这些发现在与PMN共培养的小鼠肺血管内皮细胞中得到了重现，表明内皮细胞中增强的NF-κ B活化和由此产生的TLR 2上调继发于PMN NADPH氧化酶产生的氧化剂信号传导。NADPH氧化酶介导TLR 4诱导的TLR 2在内皮细胞中的表达的功能相关性是明显的ICAM-1表达的显着升高和稳定，以及增强PMN迁移响应于连续的挑战与LPS和肽聚糖。因此，PMN NADPH氧化酶衍生的氧化剂信号传导是TLR 4和TLR 2之间的串扰和内皮细胞活化的控制的重要决定因素。
Interactions of polymorphonuclear neutrophils (PMNs) with endothelial cells may contribute to the activation of endothelial cell responses involved in innate immunity. We explored a novel function of PMN NADPH oxidase in the mechanism of Toll-like receptor-2 (TLR2) upregulation induced by LPS-TLR4 signaling in endothelial cells. We showed that LPS induced TLR2 up-regulation through TLR4- and MyD88-dependent signaling. In neutropenic mice, the LPS-induced NF-kB activation and TLR2 expression were significantly reduced, and both responses were restored upon repletion by PMN obtained from WT mice but not by PMNs from NADPH oxidase gp91pho(-/-) mice. These findings were recapitulated in mouse lung vascular endothelial cells cocultured with PMNs, indicating that the augmented NF-kB activation and the resultant TLR2 upregulation in endothelial cells were secondary to oxidant signaling generated by PMN NADPH oxidase. The functional relevance of NADPH oxidase in mediating TLR4-induced TLR2 expression in endothelial cells was evident by markedly elevated and stable ICAM-1 expression as well as augmented PMN migration in response to sequential challenge with LPS and peptidoglycan. Thus, PMN NADPH oxidase-derived oxidant signaling is an important determinant of the cross talk between TLR4 and TLR2 and the control of endothelial cell activation.