title: Increased ICAM-1 expression causes endothelial cell leakiness, cytoskeletal reorganization and junctional alterations.
abstract: Tumor necrosis factor (TNF)-induced ICAM-1 in endothelial cells (EC) promotes leukocyte adhesion. Here we report that ICAM-1 also effects EC barrier function. Control- or E-selectin-transduced human dermal microvascular EC (HDMEC) form a barrier to flux of proteins and to passage of current (measured as transendothelial electrical resistance or TEER). HDMEC transduced with ICAM-1 at levels comparable to that induced by TNF show reduced TEER, but do so without overtly changing their cell junctions, cell shape, or cytoskeleton organization. Higher levels of ICAM-1 further reduce TEER, increase F/G-actin ratios, rearrange the actin cytoskeleton to cause cell elongation, and alter junctional zona occludens 1 and vascular endothelial-cadherin staining. Transducing with ICAM-1 lacking an intracellular region also reduces TEER. TNF-induced changes in TEER and shape follow a similar time course as ICAM-1 induction; however, the fall in TEER occurs at lower TNF concentrations. Inhibiting NF-kappaB activation blocks ICAM-1 induction; TEER reduction, and shape change. Specific small-interfering RNA knockdown of ICAM-1 partially inhibits TNF-induced shape change. We conclude that moderately elevated ICAM-1 expression reduces EC barrier function and that expressing higher levels of ICAM-1 affects cell junctions and the cytoskeleton. Induction of ICAM-1 may contribute to but does not fully account for TNF-induced vascular leak and EC shape change.
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Clark
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Manes
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Pober
authors.forename: Martin S
authors.initials: MS
authors.lastname: Kluger
mesh_terms: D022005:Adherens Junctions / Q000648:ultrastructure; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000648:ultrastructure; D017097:Electric Impedance; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D007365:Intercellular Junctions / Q000502:physiology; D008833:Microcirculation; D012867:Skin / Q000098:blood supply*; D019108:Tight Junctions / Q000648:ultrastructure; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1