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.
Original language | American English |
---|---|
Journal | Journal of Cell Science |
Volume | 127 |
Issue number | 8 |
DOIs | |
State | Published - 15 Apr 2014 |
Externally published | Yes |
Keywords
- FoxO1
- IL-1β
- blood-brain barrier
- claudin-5
- non muscle myosin light chain kinase
- β-catenin
EGS Disciplines
- Biochemistry, Biophysics, and Structural Biology