title: Immobilized stromal cell-derived factor-1alpha triggers rapid VLA-4 affinity increases to stabilize lymphocyte tethers on VCAM-1 and subsequently initiate firm adhesion.
abstract: The integrin VLA-4 (alpha(4)beta(1)) mediates tethering and rolling events as well as firm adhesion of leukocytes to VCAM-1. Unlike selectins, VLA-4 integrin-mediated lymphocyte adhesiveness can be modulated by chemokines through intracellular signaling pathways. To investigate the effects of the chemokine stromal cell-derived factor-1alpha (SDF-1alpha) on VLA-4-mediated lymphocyte adhesion, human PBL were flowed over VCAM-1 substrates in a parallel plate flow chamber with surface-immobilized SDF-1alpha, a potent activator of firm adhesion. The initial tethering interactions had a median lifetime of 200 ms, consistent with the half-life of low-affinity VLA-4-VCAM-1 bonds. Immobilized SDF-1alpha acted within the lifetime of a primary tether to stabilize initial tethering interactions, increasing the likelihood a PBL would remain interacting with the surface. As expected, the immobilized SDF-1alpha also increased the ratio of PBL firm adhesion to rolling. An LDV peptide-based small molecule that preferentially binds high-affinity VLA-4 reduced PBL firm adhesion to VCAM-1 by 90%. The reduction in firm adhesion due to blockage of high-affinity VLA-4 was paralleled by a 4-fold increase in the fraction of rolling PBL. Chemokine activation of PBL firm adhesion on VCAM-1 depended on induction of high-affinity VLA-4 rather than recruitment of a pre-existing pool of high-affinity VLA-4 as previously thought.
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: DiVietro
authors.forename: David C
authors.initials: DC
authors.lastname: Brown
authors.forename: Larry A
authors.initials: LA
authors.lastname: Sklar
authors.forename: Richard S
authors.initials: RS
authors.lastname: Larson
authors.forename: Michael B
authors.initials: MB
authors.lastname: Lawrence
mesh_terms: D002448:Cell Adhesion / Q000502:physiology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D036904:Leukocyte Rolling / Q000502:physiology*; D008214:Lymphocytes / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D039041:Integrin alpha4beta1; D019010:Vascular Cell Adhesion Molecule-1