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Structural Recognition of a Novel Fibrinogen γ Chain Sequence (117 – 133) by Intercellular Adhesion Molecule-1 Mediates Leukocyte-Endothelium Interaction

1995; Elsevier BV; Volume: 270; Issue: 2 Linguagem: Inglês

10.1074/jbc.270.2.696

1083-351X

Dario C. Altieri, Alain Duperray, Janet Plescia, George B. Thornton, Lucia R. Languino,

Platelet Disorders and Treatments

In addition to its role in hemostasis, fibrinogen is obligatorily required to mount competent inflammatory responses in vivo. A molecular prerequisite of fibrinogen-dependent inflammation may reside in its ability to associate with intercellular adhesion molecule-1 (ICAM-1), and enhance monocyte adhesion to endothelium by bridging the two cell types. Structure-function characterization of the novel ICAM-1 recognition of fibrinogen was carried out by synthetic peptidyl mimicry of the fibrinogen γ chain. A novel peptide sequence, N 133 NQKIVNLKEKVAQLEA 133 , designated γ 3, dose-dependently inhibited (IC50 ~ 20-40 μg/ml) binding of 125 I-fibrinogen to endothelial cells or ICAM-1-expressing B lymphoblastoid Daudi cells. In contrast, none of the previously identified vascular cell fibrinogen interacting sequences was effective. Increasing concentrations of γ 3 completely inhibited fibrinogen-mediated adhesion of peripheral blood mononuclear cells or vitamin D3-differentiated monocytic HL-60 cells to endothelium, but did not affect leukocyte-endothelium interaction in the absence of fibrinogen. 125 I-Labeled γ 3 bound specifically and saturably to genetically engineered ICAM-1 transfectants, but not to control non-transfected cells, and associated with ICAM-1 on cytokine-activated endothelium with a Kd of 34 μM. Consistent with functional recognition of ICAM-1, immobilized γ 3 supported adhesion of JY lymphoblasts in a dose-dependent reaction inhibited by monoclonal antibodies to ICAM-1. We conclude that a novel fibrinogen γ 3 sequence N 133 NQKIVNLKEKVAQLEA 133 binds to ICAM-1 and modulates ICAM-1-dependent adhesion. These findings define the structural basis of fibrinogen:ICAM-1 recognition and provide a potential selective target for inhibiting fibrinogen-dependent inflammatory responses. In addition to its role in hemostasis, fibrinogen is obligatorily required to mount competent inflammatory responses in vivo. A molecular prerequisite of fibrinogen-dependent inflammation may reside in its ability to associate with intercellular adhesion molecule-1 (ICAM-1), and enhance monocyte adhesion to endothelium by bridging the two cell types. Structure-function characterization of the novel ICAM-1 recognition of fibrinogen was carried out by synthetic peptidyl mimicry of the fibrinogen γ chain. A novel peptide sequence, N 133 NQKIVNLKEKVAQLEA 133 , designated γ 3, dose-dependently inhibited (IC50 ~ 20-40 μg/ml) binding of 125 I-fibrinogen to endothelial cells or ICAM-1-expressing B lymphoblastoid Daudi cells. In contrast, none of the previously identified vascular cell fibrinogen interacting sequences was effective. Increasing concentrations of γ 3 completely inhibited fibrinogen-mediated adhesion of peripheral blood mononuclear cells or vitamin D3-differentiated monocytic HL-60 cells to endothelium, but did not affect leukocyte-endothelium interaction in the absence of fibrinogen. 125 I-Labeled γ 3 bound specifically and saturably to genetically engineered ICAM-1 transfectants, but not to control non-transfected cells, and associated with ICAM-1 on cytokine-activated endothelium with a Kd of 34 μM. Consistent with functional recognition of ICAM-1, immobilized γ 3 supported adhesion of JY lymphoblasts in a dose-dependent reaction inhibited by monoclonal antibodies to ICAM-1. We conclude that a novel fibrinogen γ 3 sequence N 133 NQKIVNLKEKVAQLEA 133 binds to ICAM-1 and modulates ICAM-1-dependent adhesion. These findings define the structural basis of fibrinogen:ICAM-1 recognition and provide a potential selective target for inhibiting fibrinogen-dependent inflammatory responses.