| First Author | Beard RS Jr | Year | 2014 |
| Journal | J Cell Sci | Volume | 127 |
| Issue | Pt 8 | Pages | 1840-53 |
| PubMed ID | 24522189 | Mgi Jnum | J:213074 |
| Mgi Id | MGI:5582853 | Doi | 10.1242/jcs.144550 |
| Citation | Beard RS Jr, et al. (2014) Non-muscle Mlck is required for beta-catenin- and FoxO1-dependent downregulation of Cldn5 in IL-1beta-mediated barrier dysfunction in brain endothelial cells. J Cell Sci 127(Pt 8):1840-53 |
| abstractText | Aberrant elevation in the levels of the pro-inflammatory cytokine interleukin-1beta (IL-1beta) contributes to neuroinflammatory diseases. Blood-brain barrier (BBB) dysfunction is a hallmark phenotype of neuroinflammation. It is known that IL-1beta 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 beta-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-1beta has been shown to mediate nmMlck-dependent barrier dysfunction in epithelia. Considering these factors, we tested the hypothesis that nmMlck modulates IL-1beta-mediated downregulation of Cldn5 in BMVECs in a manner that depends on transcriptional repression mediated by beta-catenin and FoxO1. We found that treating BMVECs with IL-1beta induced barrier dysfunction concomitantly with the nuclear translocation of beta-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 beta-catenin and FoxO1 in IL-1beta-mediated barrier dysfunction was dependent on nmMlck. |
