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*
Department of Clinical Ophthalmology, Institute of Ophthalmology, University College London, London, United Kingdom; and
Laboratoire d’Immuno-Pharmacologie Moléculaire, Institut Cochin de Génétique Moléculaire, Paris, France
Lymphocyte extravasation into the brain is mediated largely by the Ig superfamily molecule ICAM-1. Several lines of evidence indicate that at the tight vascular barriers of the central nervous system (CNS), endothelial cell (EC) ICAM-1 not only acts as a docking molecule for circulating lymphocytes, but is also involved in transducing signals to the EC. In this paper, we examine the signaling pathways in brain EC following Ab ligation of endothelial ICAM-1, which mimics adhesion of lymphocytes to CNS endothelia. ICAM-1 cross-linking results in a reorganization of the endothelial actin cytoskeleton to form stress fibers and activation of the small guanosine triphosphate (GTP)-binding protein Rho. ICAM-1-stimulated tyrosine phosphorylation of the actin-associated molecule cortactin and ICAM-1-mediated, Ag/IL-2-stimulated T lymphocyte migration through EC monolayers were inhibited following pretreatment of EC with cytochalasin D. Pretreatment of EC with C3 transferase, a specific inhibitor of Rho proteins, significantly inhibited the transmonolayer migration of T lymphocytes, endothelial Rho-GTP loading, and endothelial actin reorganization, without affecting either lymphocyte adhesion to EC or cortactin phosphorylation. These data show that brain vascular EC are actively involved in facilitating T lymphocyte migration through the tight blood-brain barrier of the CNS and that this process involves ICAM-1-stimulated rearrangement of the endothelial actin cytoskeleton and functional EC Rho proteins.
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C. Amos, I. A. Romero, C. Schultze, J. Rousell, J. D. Pearson, J. Greenwood, and P. Adamson Cross-Linking of Brain Endothelial Intercellular Adhesion Molecule (ICAM)-1 Induces Association of ICAM-1 With Detergent-Insoluble Cytoskeletal Fraction Arterioscler Thromb Vasc Biol, May 1, 2001; 21(5): 810 - 816. [Abstract] [Full Text] [PDF]
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G. P. van Nieuw Amerongen and V. W.M. van Hinsbergh Cytoskeletal Effects of Rho-Like Small Guanine Nucleotide-Binding Proteins in the Vascular System Arterioscler Thromb Vasc Biol, March 1, 2001; 21(3): 300 - 311. [Abstract] [Full Text] [PDF]
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J. S. Alexander Rho, Tyrosine Kinase, Ca2+, and Junctions in Endothelial Hyperpermeability Circ. Res., August 18, 2000; 87(4): 268 - 271. [Full Text] [PDF]
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H. E. Matheny, T. L. Deem, and J. M. Cook-Mills Lymphocyte Migration Through Monolayers of Endothelial Cell Lines Involves VCAM-1 Signaling Via Endothelial Cell NADPH Oxidase J. Immunol., June 15, 2000; 164(12): 6550 - 6559. [Abstract] [Full Text] [PDF]
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