1. ¹Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA
2. ²Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, Connecticut, USA
3. ³Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
4. ⁴Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA

Correspondence: Dr Martin S. Kluger, 295 Congress Avenue – Room 454, New Haven, Connecticut 06510, USA. E-mail: martin.kluger@yale.edu

Received 27 February 2006; Revised 6 September 2006; Accepted 2 October 2006; Published online 28 December 2006.

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-B 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.