The pleiotropic cytokine interleukin 2 (IL2) disrupts the blood-brain barrier and alters brain microcirculation, underlying vascular leak syndrome that complicates cancer immunotherapy with IL2. The microvascular effects of IL2 also play a role in the development of multiple sclerosis and other chronic neurological disorders. The mechanism of IL2-induced disruption of brain microcirculation has not been previously determined. Signaling through the IL2 receptor complex identified in brain microvascular endothelial cells leads to activation of the transcription factor, nuclear factor kappa B, resulting in expression of proinflammatory cytokines/chemokines. In parallel, IL2 induced disruption of adherens junctions, concomitant with cytoskeletal reorganization, ultimately leading to increased endothelial cell monolayer permeability. IL2-induced phosphorylation of vascular endothelial cadherin, a constituent of adherens junctions, leads to dissociation of its stabilizing adaptor partners. These results unravel the mechanism of deleterious effects induced by IL2 on brain microvascular endothelial cells and may inform the development of new measures to improve IL2 cancer immunotherapy, as well as treatments for autoimmune diseases affecting the central nervous system.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-11212016-210845 |
| Date | 30 November 2016 |
| Creators | Wylezinski, Lukasz Szczepan |
| Contributors | Alyssa Hasty, Roger Colbran, David Harrison, Luc Van Kaer |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-11212016-210845/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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