STRUCTURAL RECOGNITION OF A NOVEL FIBRINOGEN GAMMA-CHAIN SEQUENCE(117-133) BY INTERCELLULAR-ADHESION MOLECULE-1 MEDIATES LEUKOCYTE-ENDOTHELIUM INTERACTION

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 gamma chain, A novel peptide sequence, N(117)NQKIVNLKEKVAQLEA(133), designated gamma 3, dose-dependently inhibited (IC50 similar to 20-40 mu g/ml) binding of I-125 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 gamma 3 completely inhibited fibrinogen-mediated adhesion of peripheral blood mononuclear cells or vitamin D-3-differentiated monocytic HL-60 cells to endothelium, but did not affect leukocyte-endothelium interaction in the absence of fibrinogen, I-125-Labeled gamma 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 K-d of 34 mu M. Consistent with functional recognition of ICAM-1, immobilized gamma 3 supported adhesion of JY lymphoblasts in a dose-dependent reaction inhibited by monoclonal antibodies to ICAM-1. We conclude that a novel fibrinogen gamma 3 sequence N(117)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.