期刊
MICROVASCULAR RESEARCH
卷 67, 期 1, 页码 78-89出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.mvr.2003.07.001
关键词
MCP-1; blood-brain barrier; endothelial cells; tight junctions
资金
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH054718] Funding Source: NIH RePORTER
- NIMH NIH HHS [R01-MH54718] Funding Source: Medline
The chemokine monocyte chemoattractant protein (MCP-1) is recognized to mediate extravasation of mononuclear leukocytes into the brain during a variety of neuro inflammatory conditions. In large part produced by parenchymal neural cells during these disease states, it is unclear how this chemokine can stimulate the migration of circulating leukocytes that lie behind the highly impermeant blood-brain barrier (BBB). Based on the premise that disruption of tight junctions (TJs) could foster leukocyte extravasation, experiments were conducted to test the hypothesis that MCP-1 alters the expression and/or distribution of the TJ-associated proteins zonulae occludens-1 (ZO-1) and occludin in brain microvascular endothelial cells (BMEC) comprising the BBB. Exposure to MCPA caused a loss in immunostaining of ZO-1 at inter-endothelial junctional regions in both cultured BMEC and isolated brain microvessels, as well as a similar effect on occludin in cultured BMEC, but did not alter occludin staining in microvessels. In cellular fractionation experiments, ZO-1 associated predominantly with the detergent-resistant cytoskeletal framework (CSK) in both cultured BMEC and brain microvessels, while a slimmer majority of occludin partitioned with the CSK. Following MCP-1 exposure, ZO-1 was reduced in the CSK fraction of cultured BMEC and microvessels, with a shift of ZO-1 to the detergent-soluble fraction in both cases. Occludin exhibited a similar pattern of MCP-1-induced loss and shift from the CSK in cultured BMEC, but remained nearly constant in microvessels. Lastly, expression of caveolin-1, a major structural component of membrane microdomains thought to be functionally complexed with TJs, was additionally altered by MCP-1 treatment of both cultured BMEC and microvessels. These results indicate that, in addition to its chemotactic activity, MCP-1 might alter BBB integrity during CNS inflammation. (C) 2003 Elsevier Inc. All rights reserved.
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