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© The Rockefeller University Press, 0021-9525/1997//219 $5.00
The Journal of Cell Biology, Volume 139, Number 1, , 1997 219-228

Article

Novel Cytokine-independent Induction of Endothelial Adhesion Molecules Regulated by Platelet/Endothelial Cell Adhesion Molecule (CD31)



Marek Litwin*, Katherine Clark*, Leanne Noack*, Jill Furze*, Michael Berndt{ddagger}, Steven Albelda§, Mathew Vadas*, and Jennifer Gamble*

* Division of Human Immunology, Hanson Centre for Cancer Research, Institute of Medical and Veterinary Science, Adelaide, South Australia, 5000 Australia; {ddagger} Vascular Biology Laboratory, Baker Medical Research Institute, Prahran Victoria 3181; and § Director of Lung Research, Pulmonary and Critical Care Division, Department of Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104-4283

Tumor necrosis factor–{alpha}, interleukin-1, and endotoxin stimulate the expression of vascular endothelial cell (EC) adhesion molecules. Here we describe a novel pathway of adhesion molecule induction that is independent of exogenous factors, but which is dependent on integrin signaling and cell–cell interactions. Cells plated onto gelatin, fibronectin, collagen or fibrinogen, or anti-integrin antibodies, expressed increased amounts of E-selectin, vascular cell adhesion molecule–1, and intercellular adhesion molecule–1. In contrast, ECs failed to express E-selectin when plated on poly-L-lysine or when plated on fibrinogen in the presence of attachment-inhibiting, cyclic Arg-Gly-Asp peptides. The duration and magnitude of adhesion molecule expression was dependent on EC density. Induction of E-selectin on ECs plated at confluent density was transient and returned to basal levels by 15 h after plating when only 7 ± 2% (n = 5) of cells were positive. In contrast, cells plated at low density displayed a 17-fold greater expression of E-selectin than did high density ECs with 57 ± 4% (n = 5) positive for E-selectin expression 15 h after plating, and significant expression still evident 72 h after plating. The confluency-dependent inhibition of expression of E-selectin was at least partly mediated through the cell junctional protein, platelet/endothelial cell adhesion molecule–1 (PECAM-1). Antibodies against PECAM-1, but not against VE-cadherin, increased E-selectin expression on confluent ECs. Co– culture of subconfluent ECs with PECAM-1– coated beads or with L cells transfected with full-length PECAM-1 or with a cytoplasmic truncation PECAM-1 mutant, inhibited E-selectin expression. In contrast, untransfected L cells or L cells transfected with an adhesion-defective domain 2 deletion PECAM-1 mutant failed to regulate E-selectin expression. In an in vitro model of wounding the wound front displayed an increase in the number of E-selectin–expressing cells, and also an increase in the intensity of expression of E-selectin positive cells compared to the nonwounded monolayer. Thus we propose that the EC junction, and in particular, the junctional molecule PECAM-1, is a powerful regulator of endothelial adhesiveness.

Abbreviations used in this paper: CSF, colony stimulating factor; EC, endothelial cell; HUVEC, human umbilical vein endothelial cells; ICAM-1, intercellular adhesion molecule–1; IL-1 and IL-1ra, interleukin-1 and IL-1 receptor agonist; LPS, lipopolysaccharide; MFI, mean fluorescence intensity; PECAM, platelet/endothelial cell adhesion molecule; TNF-{alpha}, tumor necrosis factor-{alpha}; VCAM-1, vascular cell adhesion molecule–1.

M. Vadas and J. Gamble contributed equally to this paper.

Address all correspondence to Jennifer Gamble, Division of Human Immunology, Hanson Centre for Cancer Research, Institute of Medical and Veterinary Science, P.O. Box 14, Rundle Mall, Adelaide, South Australia, 5000 Australia. Tel. 6188-232-4092. Fax: 6188-232-4092. e-mail: jgamble@immuno.imvs


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