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 determined previously. We found that both human and murine brain microvascular endothelial cells express constituents of the
IL2 receptor complex. Then we established that signaling through this receptor complex leads to activation of the
transcription factor, nuclear factor κB, resulting in expression of proinflammatory
interleukin 6 and
monocyte chemoattractant protein 1. We also discovered that
IL2 induces disruption of adherens junctions, concomitant with cytoskeletal reorganization, ultimately leading to increased endothelial cell permeability. IL2-induced phosphorylation of
vascular endothelial cadherin (
VE-cadherin), a constituent of adherens junctions, leads to dissociation of its stabilizing adaptor partners,
p120-catenin and β-
catenin. Increased phosphorylation of
VE-cadherin was also accompanied by a reduction of Src homology 2 domain-containing
protein-tyrosine phosphatase 2, known to maintain vascular barrier function. 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.