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Epsilon-Toxin 通过依赖 Ca2+ 的方式损害 MDCK 细胞单层的屏障功能。

Epsilon-Toxin Impairs the Barrier Function in MDCK Cell Monolayers in a Ca-Dependent Manner.

机构信息

Department of Microbiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan.

Laboratory of Molecular Microbiological Science, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima 737-0112, Japan.

出版信息

Toxins (Basel). 2020 Apr 30;12(5):286. doi: 10.3390/toxins12050286.

DOI:10.3390/toxins12050286
PMID:32365779
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7291203/
Abstract

Epsilon-toxin produced by significantly contributes to the pathogeneses of enterotoxemia in ruminants and multiple sclerosis in humans. Epsilon-toxin forms a heptameric oligomer in the host cell membrane, promoting cell disruption. Here, we investigate the effect of epsilon-toxin on epithelial barrier functions. Epsilon-toxin impairs the barrier integrity of Madin-Darby Canine Kidney (MDCK) cells, as demonstrated by decreased transepithelial electrical resistance (TEER), increased paracellular flux marker permeability, and the decreased cellular localization of junctional proteins, such as occludin, ZO-1, and claudin-1. U73122, an endogenous phospholipase C (PLC) inhibitor, inhibited the decrease in TEER and the increase in the permeability of flux marker induced by epsilon-toxin. The application of epsilon-toxin to MDCK cells resulted in the biphasic formation of 1,2-diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP). U73122 blocked the formation of DAG and IP induced by the toxin. Epsilon-toxin also specifically activated endogenous PLC-γ1. Epsilon-toxin dose-dependently increased the cytosolic calcium ion concentration ([Ca]i). The toxin-induced elevation of [Ca]i was inhibited by U73122. Cofilin is a key regulator of actin cytoskeleton turnover and tight-junction (TJ) permeability regulation. Epsilon-toxin caused cofilin dephosphorylation. These results demonstrate that epsilon-toxin induces Ca influx through activating the phosphorylation of PLC-γ1 and then causes TJ opening accompanied by cofilin dephosphorylation.

摘要

由 产生的ε-毒素显著促进了反刍动物肠毒血症和人类多发性硬化症的发病机制。ε-毒素在宿主细胞膜上形成七聚体寡聚物，促进细胞破裂。在这里，我们研究了ε-毒素对上皮屏障功能的影响。ε-毒素损害 Madin-Darby 犬肾 (MDCK) 细胞的屏障完整性，表现为跨上皮电阻 (TEER) 降低、细胞旁通量标记物通透性增加以及连接蛋白如闭合蛋白、ZO-1 和 Claudin-1 的细胞定位减少。U73122，一种内源性磷脂酶 C (PLC) 抑制剂，抑制了 ε-毒素引起的 TEER 降低和通量标记物通透性增加。ε-毒素应用于 MDCK 细胞导致 1,2-二酰基甘油 (DAG) 和肌醇-1,4,5-三磷酸 (IP) 的两相形成。U73122 阻断了毒素诱导的 DAG 和 IP 的形成。ε-毒素还特异性激活内源性 PLC-γ1。ε-毒素剂量依赖性地增加细胞质钙离子浓度 ([Ca]i)。毒素诱导的 [Ca]i 升高被 U73122 抑制。丝切蛋白是肌动蛋白细胞骨架周转和紧密连接 (TJ) 通透性调节的关键调节剂。ε-毒素引起丝切蛋白去磷酸化。这些结果表明，ε-毒素通过激活 PLC-γ1 的磷酸化诱导 Ca 内流，然后导致 TJ 开放，同时伴有丝切蛋白去磷酸化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a71e/7291203/f59449af439a/toxins-12-00286-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a71e/7291203/31a18698287e/toxins-12-00286-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a71e/7291203/b18da9e4a181/toxins-12-00286-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a71e/7291203/ee1624e99f3a/toxins-12-00286-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a71e/7291203/f59449af439a/toxins-12-00286-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a71e/7291203/31a18698287e/toxins-12-00286-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a71e/7291203/b18da9e4a181/toxins-12-00286-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a71e/7291203/ee1624e99f3a/toxins-12-00286-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a71e/7291203/f59449af439a/toxins-12-00286-g004.jpg

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Mult Scler. 2019 Apr;25(5):653-660. doi: 10.1177/1352458518767327. Epub 2018 Apr 21.
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