Induced B7-H1 expression on human renal tubular epithelial cells by the sublytic terminal complement complex C5b-9
Induced B7-H1 expression on human renal tubular epithelial cells by the sublytic terminal complement complex C5b-9
复制标题
通过亚裂解性末端补体复合物 C5b-9 在人肾小管上皮细胞上诱导 B7-H1 表达。
DOI：
10.1016/j.molimm.2008.10.026
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发表时间：
2009-01-01
影响因子：
3.6
通讯作者：
Wu, Yuzhang
中科院分区：
文献类型：
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作者：
Chen, Yongwen;Zhang, Jingbo;Wu, Yuzhang
共抑制分子B7-H1在人炎性肾小管上皮细胞（TECs）中被广泛检测到，并被认为通过下调小管间质浸润T细胞的激活来限制小管损伤。然而，在tec中启动B7-H1表达的因素尚不清楚。终末补体复合物C5b-9弥漫性沉积在病变肾脏的小管和肾小球上，现在被认为是触发细胞活化而不是诱导细胞死亡的介质。小管上B7-H1的上调是否也被C5b-9诱导尚不确定。本研究基于纯化的补体组分，将功能性亚裂解的C5b-9组装在TECs的膜上，发现C5b-9增强了B7-H1基因的转录和蛋白合成。启动子构建的荧光素酶实验、定点诱变和激光扫描共聚焦显微镜实验（LSCM）显示，转录因子NF-kappa B主要负责c5b -9介导的B7-H1表达。为了进一步检测B7-H1的生理功能，用B7-H1激动剂mAb（克隆5H1）触发B7-H1，可以显著增强c5b -9处理的TEC细胞Fas表达，从而诱导TEC细胞凋亡。有趣的是。用Fas阻断抗体预处理tec可阻止这种作用。我们的研究结果表明，C5b-9除了直接促进小管损伤外，还可能通过增强B7-H1信号介导的细胞凋亡来调节肾小球肾炎或其他肾脏自身免疫性疾病的小管发病机制。(C) 2008 Elsevier Ltd版权所有。
The co-inhibitory molecule B7-H1 has been broadly detectable on human inflammatory renal tubular epithelial cells (TECs) and is proposed to limit tubular damage through down-regulation of tubulointerstitial infiltration T cell activation. Nevertheless, factors that initiate B7-H1 expression on TECs remain unclarified. The terminal complement complex C5b-9, which deposits diffusely On tubules and glomerules of diseased kidneys, is now recognized as a mediator that triggers cellular activation rather than inducing cell death. Whether the up-regulation of B7-H1 On tubules is also induced by C5b-9 is uncertain. Here, after assembling functional sublytic C5b-9 on the membranes of TECs based on purified complement components, we found that B7-H1 gene transcription and protein synthesis was enhanced by C5b-9. Promoter constructs in a luciferase assay, site-directed mutagenesis and laser scanning confocal microscopy assay (LSCM) revealed that the transcription factor NF-kappa B is primarily responsible for C5b-9-mediated B7-H1 expression. To further detect the physiologic function of B7-H1, triggering B7-H1 with its agonist mAb (clone 5H1) profoundly enhanced Fas expression on C5b-9-treated TECs and thus induced TEC apoptosis. Interestingly. pretreatment of TECs with Fas blocking antibodies prevented this effect. Our results propose that C5b-9 regulates tubular pathogenesis in glomerulonephritis or other renal autoimmune diseases, possibly through enhances cell apoptosis mediated by B7-H1 signals, in addition to it directly promotes tubular damage. (C) 2008 Elsevier Ltd. All rights reserved.