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The Journal of Neuroscience, November 2, 2005, 25(44):10094-10100; doi:10.1523/JNEUROSCI.3382-05.2005
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Neurobiology of Disease
Tumor Necrosis Factor-Like Weak Inducer of Apoptosis Increases the Permeability of the Neurovascular Unit through Nuclear Factor- B Pathway Activation
Rohini Polavarapu,1
Maria Carolina Gongora,1
Jeffrey A. Winkles,2 and
Manuel Yepes1
1Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322, and 2Departments of Surgery and Physiology and the Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland 21201
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily. TWEAK acts on responsive cells via binding to a small cell-surface receptor named fibroblast growth factor-inducible-14 (Fn14). TWEAK can stimulate numerous cellular responses including cell proliferation, migration, and proinflammatory molecule production. The present study investigated whether TWEAK plays a role in the regulation of the permeability of the neurovascular unit (NVU). We found that intracerebral injection of TWEAK in wild-type mice induces activation of the nuclear factor- B (NF-B) pathway and matrix metalloproteinase-9 (MMP-9) expression in the brain with resultant disruption in the structure of the NVU and increase in the permeability of the blood-brain barrier (BBB). TWEAK did not increase MMP-9 activity or BBB permeability when injected into mice genetically deficient in the NF-B family member p50. Furthermore, we report that inhibition of TWEAK activity during cerebral ischemia with an Fn14-Fc decoy receptor results in significant preservation of the integrity of the NVU with attenuation of cerebral ischemia-induced increase in the permeability of the BBB. We conclude that the cytokine TWEAK plays a role in the disruption of the structure and permeability of the NVU during physiological and pathological conditions.
Key words: TWEAK; NF-B; neurovascular unit; blood-brain barrier; matrix metalloproteinase-9; cerebral ischemia
Received June 14, 2005;
revised September 19, 2005;
accepted September 23, 2005.
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