Non-Muscle Mlck Is Required for β-catenin- and FoxO1-Dependent Downregulation of Cldn5 in IL-1β-mediated Barrier Dysfunction in Brain Endothelial CellsJournal of Cell Science (2014)
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.
- non muscle myosin light chain kinase,
- blood-brain barrier
Publication DateApril 15, 2014
Citation InformationRichard 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/