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Article
Non-Muscle Mlck Is Required for β-catenin- and FoxO1-Dependent Downregulation of Cldn5 in IL-1β-mediated Barrier Dysfunction in Brain Endothelial Cells
Journal of Cell Science
(2014)
Abstract
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-1β induced barrier dysfunction concomitantly with the nuclear translocation of b-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.
Keywords
- non muscle myosin light chain kinase,
- claudin-5,
- FoxO1,
- IL-1β,
- β-catenin,
- blood-brain barrier
Disciplines
Publication Date
April 15, 2014
DOI
10.1242/jcs.144550
Publisher Statement
For complete list of authors, please see article.
Citation Information
Richard S. Beard. "Non-Muscle Mlck Is Required for β-catenin- and FoxO1-Dependent Downregulation of Cldn5 in IL-1β-mediated Barrier Dysfunction in Brain Endothelial Cells" Journal of Cell Science Vol. 127 Iss. 8 (2014) p. 1840 - 1853 ISSN: 1477-9137 Available at: http://works.bepress.com/richard-beard/16/