| Autor: |
Beard, Jr, Richard S., Haines, Ricci J., Wu, Kevin Y., Reynolds, Jason J., Davis, Stephanie M., Elliott, John E., Malinin, Nikolay L., Chatterjee, Victor, Cha, Byeong J., Wu, Mack H., Yuan, Sarah Y. |
| Předmět: |
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| Zdroj: |
Journal of Cell Science; 2014, Vol. 127 Issue 8, p1840-1853, 14p |
| Abstrakt: |
Aberrant elevation in the levels of the pro-inflammatory cytokine interleukin-1β (IL-1β) contributes to neuroinflammatory diseases. Blood-brain barrier (BBB) dysfunction is a hallmark phenotype of neuroinflammation. It is known that IL-1β directly induces BBB hyperpermeability but the mechanisms remain unclear. Claudin-5 (Cldn5) is a tight junction protein found at endothelial cell-cell contacts that are crucial for maintaining brain microvascular endothelial cell (BMVEC) integrity. Transcriptional regulation of Cldn5 has been attributed to the transcription factors β-catenin and forkhead box protein O1 (FoxO1), and the signaling molecules regulating their nuclear translocation. Non-muscle myosin light chain kinase (nmMlck, encoded by the Mylk gene) is a key regulator involved in endothelial hyperpermeability, and IL-1β has been shown to mediate nmMlck-dependent barrier dysfunction in epithelia. Considering these factors, we tested the hypothesis that nmMlck modulates IL-1β-mediated downregulation of Cldn5 in BMVECs in a manner that depends on transcriptional repression mediated by β-catenin and FoxO1. We found that treating BMVECs with IL-1 b induced barrier dysfunction concomitantly with the nuclear translocation of β-catenin and FoxO1 and the repression of Cldn5. Most importantly, using primary BMVECs isolated from mice null for nmMlck, we identified that Cldn5 repression caused by β-catenin and FoxO1 in IL-1β-mediated barrier dysfunction was dependent on nmMlck. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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