title: Interaction of very late antigen-4 with VCAM-1 supports transendothelial chemotaxis of monocytes by facilitating lateral migration.
abstract: The transient regulation of very late antigen (VLA)-4 avidity by CC chemokines may promote chemotaxis of monocytes across VCAM-1-bearing barriers, whereas late and prolonged activation of VLA-5 may mediate subsequent localization in the extracellular matrix. We demonstrate that interactions of VLA-4 with VCAM-1, fibronectin, or a 40-kDa fragment but not a 120-kDa fragment of fibronectin supported the lateral random migration of isolated blood monocytes induced by CC chemokines, termed chemokinesis. This effect was optimal at intermediate substrate concentrations. Moreover, coimmobilization of VCAM-1 with ICAM-1 allowed better migration than ICAM-1 alone. Chemokinesis on VCAM-1 appeared to be associated with transient regulation of VLA-4 avidity by CC chemokines, given that locking VLA-4 in a high avidity state markedly inhibited migration and the locomotion rate was inversely correlated with the adhesive strength of VLA-4 to VCAM-1 following stimulation with monocyte chemoattractant protein-1. Induction of VCAM-1 expression by endothelial activation with IL-4 improved chemokinesis and lateral migration toward a monocyte chemoattractant protein-1 or a monocyte inflammatory protein-1alpha gradient on endothelium and increased transendothelial chemotaxis of monocytes by a VLA-4-dependent mechanism. In contrast, endothelial activation with IL-4 did not affect the time required for diapedesis of monocytes itself. Hence, VCAM-1 may facilitate transendothelial chemotaxis by supporting lateral migration of attached monocytes along endothelium.
authors.affiliation: Center For Blood Research and Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: C
authors.initials: C
authors.lastname: Weber
authors.forename: T A
authors.initials: TA
authors.lastname: Springer
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000494:pharmacology*; D054407:Chemokine CCL4; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000502:physiology*; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D015847:Interleukin-4 / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology*; D051379:Mice; D008954:Models, Biological; D010446:Peptide Fragments / Q000494:pharmacology; D016201:Receptors, Lymphocyte Homing / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014471:Umbilical Veins; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
chemical_list: D018932:Chemokine CCL2; D054407:Chemokine CCL4; D005353:Fibronectins; D039041:Integrin alpha4beta1; D016023:Integrins; D019402:Macrophage Inflammatory Proteins; D010446:Peptide Fragments; D016201:Receptors, Lymphocyte Homing; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D015847:Interleukin-4