Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Sci. Signal., 18 December 2012
Vol. 5, Issue 255, p. ec326
[DOI: 10.1126/scisignal.2003887]

EDITORS' CHOICE

Inflammation Disrupting the Endothelial Barrier

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

One of the hallmarks of inflammation is swelling, which results from increased permeability of the endothelial barrier, allowing fluid to flow into the tissue from the circulation. Zhu et al. found that interleukin-1β (IL-1β) caused increased permeability in cultured human dermal microvascular endothelial cells (HMVEC-d), which was associated with a reduction in the cell-surface localization of vascular endothelial cadherin (VE-cadherin). Using various inhibitors of the nuclear factor {kappa}B (NF-{kappa}B) pathway, which is activated by IL-1β, the authors ruled out a role for NF-{kappa}B signaling in contributing to enhanced HMVEC-d permeability. Targeted knockdown indicated that MyD88, an adaptor for the IL-1 receptor, was necessary for IL-1β–mediated effects on endothelial permeability, suggesting that this adaptor mediates two distinct signaling pathways, one terminating in NF-{kappa}B activation and the other in VE-cadherin internalization. IL-1β stimulated the activity of the guanosine triphosphatase ARF6, which is implicated in the internalization of adhesion proteins. The increased permeability and reduced cell-surface localization of VE-cadherin induced by IL-1β were lost in cells in which ARF6 or its activating guanine nucleotide exchange factor (GEF) ARNO, a cytohesin, was knocked down. Additionally, addition of SecinH3, an inhibitor of cytohesins, increased the cell-surface localization of VE-cadherin and prevented IL-1β–mediated loss of VE-cadherin from the surface and the increase in endothelial cell permeability. Treatment of two different mouse models of inflammation with SecinH3 reduced the severity of the inflammation without affecting global cytokine abundance, suggesting that the NF-{kappa}B arm of the system was unaffected. Whether a similar bifurcation of signaling downstream of MyD88 occurs in other types of barrier-forming cells, such as epithelial cells, and whether other adaptor proteins that couple to other receptors involved in inflammation can activate the ARF-GEF-ARF6-cadherin pathway are interesting questions.

W. Zhu, N. R. London, C. C. Gibson, C. T. Davis, Z. Tong, L. K. Sorensen. D. S. Shi, J. Guo, M. C. P. Smith, A. H. Grossmann, K. R. Thomas, D. Y. Li, Interleukin receptor activates a MYD88–ARNO–ARF6 cascade to disrupt vascular stability. Nature 492, 252–255 (2012). [PubMed]

Citation: N. R. Gough, Disrupting the Endothelial Barrier. Sci. Signal. 5, ec326 (2012).



To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882