title: Activated lymphocytes promote endothelial cell detachment from matrix: a role for modulation of endothelial cell beta 1 integrin affinity.
abstract: In vivo, MHC class I-restricted injury of allogeneic tissue or cells infected by intracellular pathogens occurs in the absence of classical cytolytic effector mechanisms and Ab. Modulation of the target cell adhesion to matrix may be an additional mechanism used to injure vascular or epithelial cells in inflammation. We studied the mechanisms of human umbilical vein endothelial cell (EC) detachment from matrix-coated plastic following contact by concanamycin A-treated lymphocytes as an in vitro model of perforin-independent modulation of EC basement membrane adhesion. Human PBL were depleted of monocytes, stimulated, then added to an EC monolayer plated on either fibronectin or type I collagen matrices. Activated, but not resting, PBL induced progressive EC detachment from the underlying matrix. Injury of the EC monolayer required direct cell contact with the activated lymphocytes because no detachment was seen when the PBL were placed above a Transwell membrane. Moreover plasma membranes prepared from activated but not resting PBL induced EC detachment. Adherent EC stimulated with activated PBL did not show evidence of apoptosis using TUNEL and annexin V staining at time points before EC detachment was observed. Finally, neither the matrix metalloproteinase inhibitors o-phenanthroline and BB-94 nor aprotinin blocked EC detachment. However, activation of EC beta1 integrin using mAb TS2/16 or Mg2+ decreased EC detachment. These data indicate that cell-cell contact between activated PBL and EC reduces adhesion of EC to the underlying matrix, at least in part by inducing changes in the affinity of the endothelial beta 1 integrin.
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Phan
authors.forename: A W
authors.initials: AW
authors.lastname: McMahon
authors.forename: R C
authors.initials: RC
authors.lastname: Nelson
authors.forename: J F
authors.initials: JF
authors.lastname: Elliott
authors.forename: A G
authors.initials: AG
authors.lastname: Murray
mesh_terms: D000276:Adjuvants, Immunologic / Q000502:physiology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology; D002448:Cell Adhesion / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000201:enzymology / Q000276:immunology* / Q000502:physiology; D005109:Extracellular Matrix / Q000201:enzymology / Q000276:immunology*; D006801:Humans; D019012:Integrin beta1 / Q000276:immunology / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008214:Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000502:physiology; D014471:Umbilical Veins
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D019012:Integrin beta1; D020782:Matrix Metalloproteinases