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肿瘤坏死因子α通过凋亡和非凋亡机制诱导脉络丛上皮细胞屏障改变。

TNFalpha induces choroid plexus epithelial cell barrier alterations by apoptotic and nonapoptotic mechanisms.

作者信息

Schwerk Christian, Rybarczyk Kasia, Essmann Frank, Seibt Annette, Mölleken Marie-Louise, Zeni Patrick, Schroten Horst, Tenenbaum Tobias

机构信息

Pediatric Infectious Diseases, Department of Pediatrics, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.

出版信息

J Biomed Biotechnol. 2010;2010:307231. doi: 10.1155/2010/307231. Epub 2010 Mar 30.

DOI:10.1155/2010/307231
PMID:20369072
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2847764/
Abstract

The choroid plexus epithelium constitutes the structural basis of the blood-cerebrospinal fluid barrier. Since the cytokine TNFalpha is markedly increased during inflammatory diseases in the blood and the central nervous system, we investigated by which mechanisms TNFalpha induces barrier alteration in porcine choroid plexus epithelial cells. We found a dose-dependent decrease of transepithelial electrical resistance, increase of paracellular inulin-flux, and induction of histone-associated DNA fragmentation and caspase-3 activation after TNFalpha stimulation. This response was strongly aggravated by the addition of cycloheximide and could partially be inhibited by the NF-kappaB inhibitor CAPE, but most effectively by the pan-caspase-inhibitor zVAD-fmk and not by the JNK inhibitor SP600125. Partial loss of cell viability could also be attenuated by CAPE. Immunostaining showed cell condensation and nuclear binding of high-mobility group box 1 protein as a sign of apoptosis after TNFalpha stimulation. Taken together our findings indicate that TNFalpha compromises PCPEC barrier function by caspase and NF-kappaB dependent mechanisms.

摘要

脉络丛上皮构成了血脑脊髓液屏障的结构基础。由于细胞因子TNFα在血液和中枢神经系统的炎症性疾病期间显著增加，我们研究了TNFα通过何种机制诱导猪脉络丛上皮细胞的屏障改变。我们发现，TNFα刺激后，跨上皮电阻呈剂量依赖性降低，细胞旁菊粉通量增加，组蛋白相关DNA片段化和caspase-3激活被诱导。加入放线菌酮后，这种反应强烈加剧，NF-κB抑制剂CAPE可部分抑制该反应，但最有效的是泛caspase抑制剂zVAD-fmk，而JNK抑制剂SP600125则无效。CAPE也可减轻部分细胞活力丧失。免疫染色显示，TNFα刺激后，细胞凝聚以及高迁移率族蛋白B1的核结合是细胞凋亡的标志。综上所述，我们的研究结果表明，TNFα通过caspase和NF-κB依赖性机制损害脉络丛上皮细胞屏障功能。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e34/2847764/5323bd429df5/JBB2010-307231.008.jpg
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