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Avidity Modulation Activates Adhesion under Flow and Requires Cooperativity among Adhesion Receptors

Na Ni ^*, Christopher G. Kevil , Daniel C. Bullard  and Dennis F. Kucik  ^* ¶

Departments of Genomics and Pathobiology, and Pathology, and ^* Biomedical Engineering, University of Alabama at Birmingham, Birmingham, Alabama 35294; Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130; and ^¶ Research Service, Birmingham VA Medical Center, Birmingham, Alabama 35233

Correspondence: Address reprint requests to Dennis F. Kucik, MD, PhD, University of Alabama at Birmingham, Center for Biophysical Sciences and Engineering (CBSE), Rm. 258, 1025 18th St., South Birmingham, AL 35294. Tel.: 205-934-0062; Fax: 205-934-0480; E-mail: kucik{at}uab.edu.

An early step in activation of leukocyte adhesion is a release of integrins from cytoskeletal constraints on their diffusion, leading to rearrangement and, consequently, increased avidity. Static adhesion assays using purified ligand as a substrate have demonstrated that very low doses of cytochalasin D disconnect ß₂-integrins from their cytoskeletal links, allowing rearrangement and activating adhesion. The adhesion process in blood vessels is poorly simulated by these assays, however, for two reasons: leukocyte adhesion to endothelium 1), occurs in the presence of blood flow and 2), involves the simultaneous interactions of multiple sets of adhesion molecules. We investigated the effect of cytochalasin D, at concentrations that increase integrin diffusion but do not alter leukocyte shape and surface features, on adhesion of leukocytes to endothelial cells under flow. Cytochalasin D increased the number of rolling cells, the number of firmly adherent cells, and the duration of both rolling and firm adhesion. These effects required endothelial cell expression of ICAM-1, the ligand for leukocyte ß₂-integrins. The ß₂-integrin–ICAM-1 interaction alone was not sufficient, however. Experiments using purified substrates demonstrated that avidity effects on activation of adhesion under flow require functional cooperativity between integrins and other adhesion receptors.

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