Shiga-like toxin inhibition of FLICE-like inhibitory protein expression sensitizes endothelial cells to bacterial lipopolysaccharide-induced apoptosis
Shiga-like toxin inhibition of FLICE-like inhibitory protein expression sensitizes endothelial cells to bacterial lipopolysaccharide-induced apoptosis
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DOI：
10.1074/jbc.m206351200
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发表时间：
2002-10-25
影响因子：
4.8
通讯作者：
Bannerman, DD
中科院分区：
文献类型：
--
作者：
Erwert, RD;Winn, RK;Bannerman, DD
志贺样毒素（Shiga-like toxin，SHI）与溶血性尿毒症综合征的发病机制及其伴随的内皮细胞损伤有关。大肠杆菌的关键血清型除了产生另一种高度促炎分子脂多糖（LPS）外，还产生β-内酰胺酶-1。先前已经确定，LPS-1诱导EC凋亡，并且LPS增强这种作用。单独的LPS对人EC活力没有影响，并且这种增强的机制仍然未知。在本报告中，我们证明，ESTA-1敏感EC LPS诱导的细胞凋亡。LPS预处理对EC诱导的细胞凋亡无影响，而LPS预处理对EC诱导的细胞凋亡无影响。FLICE-1暴露导致FLICE样抑制蛋白（FLIP）的表达减少，FLIP是一种抗凋亡蛋白，以前已被证明可以阻断LPS诱导的细胞凋亡。FLIP表达的这种ESTA-1介导的减少之前，由ESTA-1单独或与LPS组合引起的细胞凋亡的发作。FLIP表达的抑制与LPS诱导的细胞凋亡敏感性呈剂量和时间依赖性。最后，瞬时或稳定的过表达FLIP保护LPS增强IL-1诱导的细胞凋亡，这种保护与FLIP的持续表达相对应。总之，这些数据表明，EST-I通过抑制FLIP表达而使EC对LPS诱导的细胞凋亡敏感。
Shiga-like toxin (SLT) has been implicated in the pathogenesis of hemolytic uremic syndrome and its attendant endothelial cell (EC) injury. Key serotypes of Escherichia coli produce SLT-1 in addition to another highly pro-inflammatory molecule, lipopolysaccharide (LPS). It has previously been established that SLT-1 induces EC apoptosis and that LPS enhances this effect. LPS alone has no affect on human EC viability, and the mechanism for this enhancement remains unknown. In the present report, we demonstrate that SLT-1 sensitizes EC to LPS-induced apoptosis. Pretreatment with SLT-1 sensitized EC to LPS-induced apoptosis, whereas pretreatment with LPS did not influence SLT-1-induced apoptosis. SLT-1 exposure resulted in decreased expression of FLICE-like inhibitory protein (FLIP), an antiapoptotic protein that has previously been shown to block LPS-induced apoptosis. This SLT-1-mediated decrease in FLIP expression preceded the onset of apoptosis elicited by SLT-1 alone or in combination with LPS. SLT-1-mediated decrements in FLIP expression correlated in a dose- and time-dependent manner with sensitization to LPS-induced apoptosis. Finally, transient or stable overexpression of FLIP protected against LPS enhancement of SLT-1-induced apoptosis, and this protection corresponded with sustained expression of FLIP. Together, these data suggest that SLT-1 sensitizes EC to LPS-induced apoptosis by inhibiting FLIP expression.