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Original Article

Subsecond Induction of 4 Integrin Clustering by Immobilized Chemokines Stimulates Leukocyte Tethering and Rolling on Endothelial Vascular Cell Adhesion Molecule 1 under Flow Conditions

^a Department of Immunology, The Weizmann Institute of Science, Rehovot, 76100 Israel
^b Department of Tumor Immunology, University Hospital Nijmegen, Nijmegen 6525 EX, The Netherlands
^c Unite d'Immunologie Virale, Institute Pasteur, 75724 Paris, France
^d Biogen, Incorporated, Cambridge, Massachusetts 02142
Dept. of Immunology, The Weizmann Institute of Science, Rehovot, 76100 Israel.972-8-9344141972-8-9342482

ronalon{at}weizmann.weizmann.ac.il

Leukocyte recruitment to target tissue is initiated by weak rolling attachments to vessel wall ligands followed by firm integrin-dependent arrest triggered by endothelial chemokines. We show here that immobilized chemokines can augment not only arrest but also earlier integrin-mediated capture (tethering) of lymphocytes on inflamed endothelium. Furthermore, when presented in juxtaposition to vascular cell adhesion molecule 1 (VCAM-1), the endothelial ligand for the integrin very late antigen 4 (VLA-4, 4β1), chemokines rapidly augment reversible lymphocyte tethering and rolling adhesions on VCAM-1. Chemokines potentiate VLA-4 tethering within <0.1 s of contact through Gi protein signaling, the fastest inside-out integrin signaling events reported to date. Although VLA-4 affinity is not altered upon chemokine signaling, subsecond VLA-4 clustering at the leukocyte-substrate contact zone results in enhanced leukocyte avidity to VCAM-1. Endothelial chemokines thus regulate all steps in adhesive cascades that control leukocyte recruitment at specific vascular beds.

Key Words: adhesion • integrin • endothelium • chemokine • shear flow

Abbreviations used in this paper: CHO, Chinese hamster ovary; EC, endothelial cell; ECL, EBI1 ligand chemokine; GPCRs, Gi protein–coupled receptors; HPC, hematopoietic progenitor cell; HSA, human serum albumin; HUVEC, human umbilical cord endothelial cell; IP-10, IFN-–inducible protein 10; PBTL, peripheral blood T lymphocyte; PTX, pertussis toxin; RANTES, regulated on activation, normal T cell expressed and secreted; SDF-1, stromal derived factor 1; SLC, secondary lymphoid tissue chemokine; VCAM, vascular cell adhesion molecule; VLA-4, very late antigen 4.

© 2000 The Rockefeller University Press

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This article has been cited by other articles:

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• Poon, B. Y., Ward, C. A., Cooper, C. B., Giles, W. R., Burns, A. R., Kubes, P. (2001). {alpha}4-Integrin Mediates Neutrophil-Induced Free Radical Injury to Cardiac Myocytes. JCB 152: 857-866 [Abstract] [Full Text]  

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