title: Divergent effects of platelet-endothelial cell adhesion molecule-1 and beta 3 integrin blockade on leukocyte transmigration in vivo.
abstract: The final stage in the migration of leukocytes to sites of inflammation involves movement of leukocytes through the endothelial cell layer and the perivascular basement membrane. Both platelet-endothelial cell adhesion molecule-1 (PECAM-1/CD31) and the integrin alphavbeta3 have been implicated in this process, and in vitro studies have identified alphavbeta3 as a heterotypic ligand for PECAM-1. In the present study we have addressed the roles of these molecules by investigating and comparing the effects of PECAM-1 and alphavbeta3 blockade on leukocyte migration in vivo. For this purpose we have examined the effects of neutralizing Abs directed against PECAM-1 (domain 1-specific, mAb 37) and beta3 integrins (mAbs 7E3 and F11) on leukocyte responses in the mesenteric microcirculation of anesthetized rats using intravital microscopy. The anti-PECAM-1 mAb suppressed leukocyte extravasation, but not leukocyte rolling or firm adhesion, elicited by IL-1beta 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 neutrophil migration through the endothelial cell barrier. By contrast, both anti-beta3 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-1beta-induced leukocyte responses. These findings indicate roles for both PECAM-1 and beta3 integrins in leukocyte extravasation, but do not support the concept that these molecules act as counter-receptors in mediating leukocyte transmigration.
authors.affiliation: BHF Cardiovascular Medicine Unit, Imperial College School of Medicine at the National Heart and Lung Institute, Hammersmith Hospital, UK.
authors.forename: R D
authors.initials: RD
authors.lastname: Thompson
authors.forename: M W
authors.initials: MW
authors.lastname: Wakelin
authors.forename: K Y
authors.initials: KY
authors.lastname: Larbi
authors.forename: A
authors.initials: A
authors.lastname: Dewar
authors.forename: G
authors.initials: G
authors.lastname: Asimakopoulos
authors.forename: M A
authors.initials: MA
authors.lastname: Horton
authors.forename: M T
authors.initials: MT
authors.lastname: Nakada
authors.forename: S
authors.initials: S
authors.lastname: Nourshargh
mesh_terms: D000077284:Abciximab; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000918:Antibody Specificity; D015703:Antigens, CD / Q000276:immunology*; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology / Q000648:ultrastructure; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D039661:Integrin beta3; D007375:Interleukin-1 / Q000494:pharmacology; D007962:Leukocytes / Q000166:cytology / Q000276:immunology; D008297:Male; D008643:Mesentery / Q000098:blood supply; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000276:immunology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000276:immunology*; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D014699:Venules / Q000276:immunology / Q000648:ultrastructure
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C105869:Fab F11.2.32; D007140:Immunoglobulin Fab Fragments; D007166:Immunosuppressive Agents; D039661:Integrin beta3; D007375:Interleukin-1; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D010980:Platelet Membrane Glycoproteins; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000077284:Abciximab