Increased ICAM-1 expression causes endothelial cell leakiness, cytoskeletal reorganization and junctional alterations
Increased ICAM-1 expression causes endothelial cell leakiness, cytoskeletal reorganization and junctional alterations
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DOI：
10.1038/sj.jid.5700670
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发表时间：
2007-04-01
影响因子：
6.5
通讯作者：
Kluger, Martin S.
中科院分区：
文献类型：
--
作者：
Clark, Paul R.;Manes, Thomas D.;Kluger, Martin S.
肿瘤坏死因子 (TNF) 诱导内皮细胞 (EC) 中的 ICAM-1 促进白细胞粘附。在此我们报道 ICAM-1 也影响 EC 屏障功能。对照或 E 选择素转导的人真皮微血管 EC (HDMEC) 形成蛋白质流动和电流通过（测量为跨内皮电阻或 TEER）的屏障。用 ICAM-1 转导的 HDMEC 的水平与 TNF 诱导的水平相当，显示 TEER 降低，但这样做不会明显改变其细胞连接、细胞形状或细胞骨架组织。较高水平的 ICAM-1 进一步降低 TEER，增加 F/G-肌动蛋白比率，重新排列肌动蛋白细胞骨架以引起细胞伸长，并改变交界带闭塞 1 和血管内皮钙粘蛋白染色。用缺乏细胞内区域的 ICAM-1 进行转导也会降低 TEER。 TNF 诱导的 TEER 和形状变化遵循与 ICAM-1 诱导相似的时间过程；然而，TEER 下降发生在 TNF 浓度较低时。抑制 NF-kappa B 激活可阻断 ICAM-1 诱导； TEER 减少，形状改变。 ICAM-1 的特异性小干扰 RNA 敲低可部分抑制 TNF 诱导的形状变化。我们得出的结论是，适度升高的 ICAM-1 表达会降低 EC 屏障功能，并且表达较高水平的 ICAM-1 会影响细胞连接和细胞骨架。 ICAM-1 的诱导可能有助于但不能完全解释 TNF 诱导的血管渗漏和 EC 形状的变化。
Tumor necrosis factor (TNF)-induced ICAM-1 in endothelial cells (EC) promotes leukocyte adhesion. Here we report that ICAM-1 also effects EC barrier function. Control- or E-selectin-transduced human dermal microvascular EC (HDMEC) form a barrier to flux of proteins and to passage of current (measured as transendothelial electrical resistance or TEER). HDMEC transduced with ICAM-1 at levels comparable to that induced by TNF show reduced TEER, but do so without overtly changing their cell junctions, cell shape, or cytoskeleton organization. Higher levels of ICAM-1 further reduce TEER, increase F/G-actin ratios, rearrange the actin cytoskeleton to cause cell elongation, and alter junctional zona occludens 1 and vascular endothelial-cadherin staining. Transducing with ICAM-1 lacking an intracellular region also reduces TEER. TNF-induced changes in TEER and shape follow a similar time course as ICAM-1 induction; however, the fall in TEER occurs at lower TNF concentrations. Inhibiting NF-kappa B activation blocks ICAM-1 induction; TEER reduction, and shape change. Specific small-interfering RNA knockdown of ICAM-1 partially inhibits TNF-induced shape change. We conclude that moderately elevated ICAM-1 expression reduces EC barrier function and that expressing higher levels of ICAM-1 affects cell junctions and the cytoskeleton. Induction of ICAM-1 may contribute to but does not fully account for TNF-induced vascular leak and EC shape change.