Divergent effects of platelet-endothelial cell adhesion molecule-1 and beta(3) integrin blockade on leukocyte transmigration in vivo

The final stage in the migration of leukocytes to sites of inflammation inv olves movement of leukocytes through the endothelial cell layer and the per ivascular basement membrane. Both platelet-endothelial cell adhesion molecu le-1 (PECAM-1/CD31) and the integrin alpha(v)beta(3) have been implicated i n this process, and in vitro studies have identified alpha(v)beta(3) as a h eterotypic ligand for PECAM-1. In the present study we have addressed the r oles of these molecules by investigating and comparing the effects of PECAM -1 and alpha(v)beta(3) blockade on leukocyte migration in vivo. For this pu rpose we have examined the effects of neutralizing Abs directed against PEC AM-1 (domain 1-specific, mAb 37) and beta(3) integrins (mAbs 7E3 and F11) o n leukocyte responses in the mesenteric microcirculation of anesthetized ra ts using intravital microscopy. The anti-PECAM-1 mAb suppressed leukocyte e xtravasation, but not leukocyte rolling or firm adhesion, elicited by IL-1 beta in a dose-dependent manner (e.g., 67% inhibition at 10 mg/kg 37 Fab), but had no effect on FMLP-induced leukocyte responses. Analysis by electron microscopy suggested that this suppression was due to an inhibition of neu trophil migration through the endothelial cell barrier, By contrast, both a nti-beta(3) integrin mAbs, 7E3 F(ab')(2) (5 mg/kg) and F11 F(ab')(2) (5 mg/ kg), selectively reduced leukocyte extravasation induced by FMLP (38 and 46 %, respectively), but neither mAb had an effect on IL-1 beta-induced leukoc yte responses. These Endings indicate roles for both PECAM-1 and beta(3) in tegrins in leukocyte extravasation, but do not support the concept that the se molecules act as counter-receptors in mediating leukocyte transmigration .