title: Critical role of P-selectin-dependent rolling in tumor necrosis factor-alpha-induced leukocyte adhesion and extravascular recruitment in vivo.
abstract: Leukocyte-endothelium interactions are dependent on a coordinated expression and function of specific adhesion molecules. The objective of the present study was to examine the role of selectin function and leukocyte rolling in tumor necrosis factor-alpha (TNF-alpha)-induced leukocyte adhesion and extravasation in venules in vivo. For this purpose, we used intravital microscopy in the mouse cremaster muscle stimulated for 2-3 h with TNF-alpha intrascrotally. Pretreatment with fucoidan, which inhibits P- and L-selectin, and a P-selectin monoclonal antibody (RB40.34) abolished TNF-alpha-stimulated leukocyte rolling. This great reduction in rolling caused a marked attenuation of firm adhesion and extravascular accumulation of leukocytes. When fucoidan and RB40.34 were administrated after stimulation with TNF-alpha, it was found that leukocyte rolling was greatly reduced whereas the number of firmly adherent leukocytes was completely unchanged, suggesting that the inhibitory effect of blocking P-selectin function on firm leukocyte adhesion and recruitment was due to the reduction in leukocyte rolling along the endothelium. Moreover, pretreatment with a monoclonal antibody against intercellular adhesion molecule-1 (ICAM-1) and a platelet-activating factor (PAF)-receptor antagonist had no effect of TNF-alpha-induced leukocyte rolling and adhesion, indicating that molecules other than ICAM-1 and PAF mediate firm adhesion and recruitment of leukocytes in TNF-alpha-activated tissues. Taken together, our data demonstrate that P-selectin function plays an important role in TNF-alpha-induced inflammatory cell recruitment by mediating leukocyte rolling as a precondition for cytokine-provoked firm adhesion and transmigration in vivo. These findings, thus, suggest that inhibition of P-selectin may be a central target for pharmacological intervention in inflammatory diseases.
authors.affiliation: Department of Surgery, Malmö University Hospital, Lund University, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Månsson
authors.forename: X W
authors.initials: XW
authors.lastname: Zhang
authors.forename: B
authors.initials: B
authors.lastname: Jeppsson
authors.forename: O
authors.initials: O
authors.lastname: Johnell
authors.forename: H
authors.initials: H
authors.lastname: Thorlacius
mesh_terms: D000268:Adhesiveness / Q000187:drug effects; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D002464:Cell Migration Inhibition; D066298:In Vitro Techniques; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000033:anatomy & histology / Q000166:cytology; D019007:P-Selectin / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; D019007:P-Selectin; D014409:Tumor Necrosis Factor-alpha