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Endothelial cell adhesion molecules: expression, upregulation and modulation of human brain microvessel endothelial cell-leukocyte interactions

University of British Columbia

Endothelial cells (EC) lining the cerebral blood vessels are responsible for the formation and maintenance of a unique structural and functional barrier, the blood-brain barrier (BBB), that normally prevents the movement of white blood cells from blood into brain. Inflammatory and infectious diseases of the central nervous system (CNS), including multiple sclerosis, encephalitis, meningitis and infarction, are characterized by increased BBB permeability and infiltration of the brain by leukocytes. The mechanisms that regulate the traffic of leukocytes across the BBB have not yet been elucidated. A group of EC surface molecules called adhesion molecules, have been implicated in interactions between inflammatory cells and extracerebral EC. They include E-selectin, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and platelet/endothelial cell adhesion molecule-1 (PECAM-1). Blocking these molecules with antibodies (Abs) reduces leukocyte traffic across EC. One of these molecules, ICAM-1, has been demonstrated in inflammatory CNS lesions. The objective of this study was to investigate the expression and function of four EC adhesion molecules in an in vitro model of the human BBB. The results indicate that primary cultures of unstimulated human brain microvessel EC (HBMEC) form high resistance monolayers and express low levels of E-selectin, VCAM-1 and ICAM-1 that can be significantly upregulated following stimulation with cytokines and LPS. PECAM-1 is strongly expressed by all cells constitutively. Treatment of HBMEC with TNF increases monolayer permeability, and augments adhesion and migration of polymorphonuclear leukocytes (PMN) and T-lymphocytes across the monolayers. Adhesion of resting T-lymphocytes to activated endothelium is mediated by VCAM-1 and ICAM-1. ICAM-1, E-selectin and PECAM-1 participate in T-lymphocyte migration across HBMEC monolayers. Adhesion of PMN to activated HBMEC is mediated by ICAM-1 and E-selectin, while ICAM-1 is involved in the migration process. Anti-adhesion molecule Abs reduce adhesion and/or migration but have no effect on the increased endothelial permeability secondary to leukocyte migration. These studies indicate that EC adhesion molecules, induced by cytokines, mediate cerebral EC-leukocyte interactions which, in association with a concurrent increase in endothelial permeability, may facilitate leukocyte traffic across the BBB in the early stages of CNS inflammation.

Thesis/Dissertation

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2009-06-04

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http://hdl.handle.net/2429/8732

Pathology

University of British Columbia

UBCV

DSpace