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Title page for ETD etd-11212016-210845


Type of Document Dissertation
Author Wylezinski, Lukasz Szczepan
Author's Email Address lukasz.s.wylezinski@vanderbilt.edu
URN etd-11212016-210845
Title Activation and Disruption of Brain Microvascular Endothelial Cells by Interleukin 2
Degree PhD
Department Molecular Physiology and Biophysics
Advisory Committee
Advisor Name Title
Alyssa Hasty Committee Chair
David Harrison Committee Member
Luc Van Kaer Committee Member
Roger Colbran Committee Member
Keywords
  • immunotherapy
  • permeability
  • brain microvascular endothelial cells
  • interleukin 2
  • adherens junction
Date of Defense 2016-11-17
Availability unrestricted
Abstract
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.

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