PKC and RhoA signals cross-talk in Escherichia coli endotoxin induced alterations in brain endothelial permeability
PKC and RhoA signals cross-talk in Escherichia coli endotoxin induced alterations in brain endothelial permeability
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DOI：
10.1016/j.bbrc.2012.07.063
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发表时间：
2012-08-24
影响因子：
3.1
通讯作者：
Peng, Jing
中科院分区：
文献类型：
--
作者：
He, Fang;Yin, Fei;Peng, Jing
大肠杆菌内毒素LPS通过破坏脑内皮细胞之间的紧密连接（TJ）复合物来调节血脑屏障的通透性。本研究利用Bend.3细胞研究了脂多糖引起的脑内皮屏障高通透性的信号网络。lps诱导的脑内皮屏障改变与PKC （a, β, zeta）和RhoA相关，但不依赖于pi3k和酪氨酸激酶途径。使用shRNA和显性阴性突变体抑制PKC （a, β, zeta）和RhoA活性，可减少LPS对脑内皮TJs的影响。因此，PKC和Rho通路之间的相互作用被检查。在LPS刺激的Bend.3细胞中，PKC-a和PKC-zeta与RhoA相互作用，但pkc - β不与RhoA相互作用。PKC-a作为Rho的上游分子，PKC-zeta作为Rho的下游靶标。比较“Rho和PKC”双重抑制和“Rho”或“PKC”单一抑制的效果，证实这种相互作用对lps诱导的脑内皮细胞高通透性至关重要。总的来说，这些数据首次表明LPS通过PKC （a， 13和RhoA）影响脑内皮TJ屏障，而不依赖于pi3k和酪氨酸激酶途径。此外，PKC-a和PKC-zeta分别作为RhoA的上游和下游调节因子。英国皇家版权所有(c) 2012出版的爱思唯尔公司。版权所有。
Escherichia coli endotoxin LPS regulates blood-brain barrier permeability by disrupting the tight junction (TJ) complex between brain endothelial cells. This study used Bend.3 cells to examine the signaling networks involved in the hyperpermeability of the brain endothelial barrier caused by LPS. The LPS-induced alterations in the brain endothelial barrier were associated with PKC (a, beta, zeta) and RhoA, but were independent of PI3 K and the tyrosine kinase pathway. Inhibition of PKC (a, beta, zeta) and RhoA activity using shRNA and dominant negative mutants diminished the effects of LPS on the brain's endothelial TJs. The interactions between the PKC and Rho pathways were therefore examined. PKC-a and PKC-zeta, but not PKC-beta interacted with RhoA in Bend.3 cells stimulated by LPS. PKC-a acted as the upstream molecule for Rho and PKC-zeta acted as the downstream target for Rho. Comparing the effect of double inhibition of "Rho and PKC" and single inhibition of "Rho" or "PKC" confirmed that this interaction is critical for LPS-induced brain endothelial cell hyperpermeability. Collectively these data are the first to suggest that LPS affects the brain's endothelial TJ barrier via PKC (a, 13, and RhoA, independent of the PI3 K and tyrosine kinase pathways. In addition, PKC-a and PKC-zeta, respectively, act as the upstream and downstream regulator for RhoA in the process. Crown Copyright (c) 2012 Published by Elsevier Inc. All rights reserved.