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Immobilized Stromal Cell-Derived Factor-1 Triggers Rapid VLA-4 Affinity Increases to Stabilize Lymphocyte Tethers on VCAM-1 and Subsequently Initiate Firm Adhesion¹

Jeffrey A. DiVietro^*, David C. Brown, Larry A. Sklar, Richard S. Larson and Michael B. Lawrence^2,*

^* Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908; and Division of Hematology/Pathology, Cancer Center, University of New Mexico, Albuquerque, NM 87112

The integrin VLA-4 (₄₁) 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-1 (SDF-1) on VLA-4-mediated lymphocyte adhesion, human PBL were flowed over VCAM-1 substrates in a parallel plate flow chamber with surface-immobilized SDF-1, 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-1 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-1 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant HL54614.

² Address correspondence and reprint requests to Dr. Michael B. Lawrence, Department of Biomedical Engineering, MR5 Building Room 2111, University of Virginia, P.O. Box 800759, Charlottesville, VA 22908. E-mail address: mbl2a{at}virginia.edu

³ Abbreviations used in this paper: SDF, stromal cell-derived factor; PTX, pertussis toxin.

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