ICAM-2 and a peptide from its binding domain are efficient activators of leukocyte adhesion and integrin affinity.
Cell adhesion mediated by the CD11/CD18 integrins and their ligands, the ICAMs, is required for many leukocyte functions. In resting cells the integrins are nonadhesive, but when activated they become adhesive for their ligands. Previous findings have shown that a peptide derived from the first Ig domain of ICAM-2 (P1) binds to LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) and activates leukocyte aggregation. Because its mechanism of action has remained poorly understood, we have now studied the peptide-induced ligand binding in detail. Here we show that P1 was able to induce CD11/CD18-dependent adhesion of human T lymphocytes to immobilized, purified ICAM-1, -2, and -3. The optimal peptide concentration was 150 micrograms/ml, whereas concentrations higher than 400 micrograms/ml did not have any stimulatory effect. The increase in adhesion was detectable within 10 min of treatment with the peptide; it was dependent on energy, divalent cations, temperature, and an intact cytoskeleton but was unaffected by protein kinase C and protein tyrosine kinase inhibitors. Peptide treatment resulted in strong stimulation of the binding of soluble, recombinant ICAMs to T lymphocytes, showing that the integrin affinity toward its ligands was increased. Importantly, soluble ICAM-2Fc was also able to induce T lymphocyte adhesion to purified ICAM-1, -2, and -3, and it was a more potent stimulatory molecule than ICAM-1Fc or ICAM-3Fc.
Kotovuori
A
A
Department of Biosciences, Division of Biochemistry, University of Helsinki, Finland.
Pessa-Morikawa
T
T
Kotovuori
P
P
Nortamo
P
P
Gahmberg
C G
CG
D000199:Actins / Q000276:immunology; D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D000943:Antigens, Differentiation; D018845:CD11 Antigens / Q000502:physiology; D018821:CD18 Antigens / Q000502:physiology; D002413:Cations, Divalent; D002448:Cell Adhesion / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D003599:Cytoskeleton / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D004734:Energy Metabolism / Q000276:immunology; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology; D013601:T-Lymphocytes / Q000502:physiology*; D013696:Temperature
D000199:Actins; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018845:CD11 Antigens; D018821:CD18 Antigens; D002413:Cations, Divalent; D015815:Cell Adhesion Molecules; C065289:ICAM2 protein, human; C483616:ICAM3 protein, human; D016023:Integrins; D010455:Peptides; D011993:Recombinant Fusion Proteins; D018799:Intercellular Adhesion Molecule-1