title: Intracellular domain of brain endothelial intercellular adhesion molecule-1 is essential for T lymphocyte-mediated signaling and migration.
abstract: To examine the role of the ICAM-1 C-terminal domain in transendothelial T lymphocyte migration and ICAM-1-mediated signal transduction, mutant human (h)ICAM-1 molecules were expressed in rat brain microvascular endothelial cells. The expression of wild-type hICAM-1 resulted in a significant increase over basal levels in both adhesion and transendothelial migration of T lymphocytes. Endothelial cells (EC) expressing ICAM-1 in which the tyrosine residue at codon 512 was substituted with phenylalanine (hICAM-1(Y512F)) also exhibited increased lymphocyte migration, albeit less than that with wild-type hICAM-1. Conversely, the expression of truncated hICAM-1 proteins, in which either the intracellular domain was deleted (hICAM-1DeltaC) or both the intracellular and transmembrane domains were deleted through construction of a GPI anchor (GPI-hICAM-1), did not result in an increase in lymphocyte adhesion, and their ability to increase transendothelial migration was attenuated. Truncated hICAM-1 proteins were also unable to induce ICAM-1-mediated Rho GTPase activation. EC treated with cell-permeant penetratin-ICAM-1 peptides comprising human or rat ICAM-1 intracellular domain sequences inhibited transendothelial lymphocyte migration, but not adhesion. Peptides containing a phosphotyrosine residue were equipotent in inhibiting lymphocyte migration. These data demonstrate that the intracellular domain of ICAM-1 is essential for transendothelial migration of lymphocytes, and that peptidomimetics of the ICAM-1 intracellular domain can also inhibit this process. Such competitive inhibition of transendothelial lymphocyte migration in the absence of an affect on adhesion further implicates ICAM-1-mediated signaling events in the facilitation of T lymphocyte migration across brain EC. Thus, agents that mimic the ICAM-1 intracellular domain may be attractive targets for novel anti-inflammatory therapeutics.
authors.affiliation: Division of Cell Biology, Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Greenwood
authors.forename: Claire L
authors.initials: CL
authors.lastname: Amos
authors.forename: Claire E
authors.initials: CE
authors.lastname: Walters
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Couraud
authors.forename: Ruth
authors.initials: R
authors.lastname: Lyck
authors.forename: Britta
authors.initials: B
authors.lastname: Engelhardt
authors.forename: Peter
authors.initials: P
authors.lastname: Adamson
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002461:Cell Line, Transformed; D002463:Cell Membrane Permeability / Q000235:genetics / Q000502:physiology; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003432:Cross-Linking Reagents / Q000378:metabolism; D003593:Cytoplasm / Q000235:genetics / Q000502:physiology; D019281:Dimerization; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007424:Intracellular Fluid / Q000502:physiology*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D017384:Sequence Deletion; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000502:physiology*
chemical_list: D003432:Cross-Linking Reagents; D010446:Peptide Fragments; D018799:Intercellular Adhesion Molecule-1