Potential role of MCP-1 in endothelial cell tight junction `opening': signaling via Rho and Rho kinase

Journal of Cell Science - Tập 116 Số 22 - Trang 4615-4628 - 2003
Svetlana M. Stamatovic1, Richard F. Keep1,2, Steven L. Kunkel3, Anuska V. Andjelkovic1,3
1Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
2Department of Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
3Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109 USA

Tóm tắt

The expression of the monocyte chemoattractant protein-1 (MCP-1) receptor CCR2 by brain endothelial cells suggests that MCP-1 may have other functions than purely driving leukocyte migration into brain parenchyma during inflammation. This study examines one of these potential novel roles of MCP-1 regulation of endothelial permeability using primary cultures of mouse brain endothelial cells. MCP-1 induces reorganization of actin cytoskeleton (stress fiber formation) and redistribution of tight junction proteins, ZO-1, ZO-2 occludin and claudin-5, from the Triton X-100-soluble to the Triton X-100-insoluble fractions. These morphological changes are associated with a decrease in transendothelial electrical membrane resistance and an increase in [14C]inulin permeability. MCP-1 did not induce these events in brain endothelial cells prepared from mice genotype CCR2–/–. The Rho kinase inhibitor Y27632 and inhibition of Rho (C3 exoenzyme, and dominant negative mutant of Rho, RhoT19N) prevented MCP-1-induced stress fiber assembly, reorganization of tight junction proteins and alterations in endothelial permeability. In all, this suggests that a small GTPase Rho and Rho kinase have a pivotal role in MCP-1-induced junction disarrangement. These data are the first to strongly suggest that MCP-1, via CCR2 present on brain endothelial cells, contributes to increased brain endothelial permeability.

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