REGULATION OF ALPHA(4) INTEGRIN-MEDIATED ADHESION OF HUMAN EOSINOPHILS TO FIBRONECTIN AND VASCULAR CELL-ADHESION MOLECULE-1

Background: Eosinophils selectively accumulate at sites of allergic in flammation. Their recruitment is dependent on both the expression and functional activity of cell adhesion molecules. How tile functional ac tivity of cell adhesion molecules on eosinophils is regulated is poorl y understood, Objective: Our objective was to examine the functional a ctivity of alpha(4) integrins on human eosinophils and its regulation by various agents. Methods: Function of alpha(4) integrins on human eo sinophils was examined by testing adhesion to immobilized fibronectin and vascular cell adhesion molecule-1 (VCAM-1) in the presence or abse nce of a monoclonal antibody (mAb) (8A2) that activates beta(perpendic ular to) integrin function, Results: Spontaneous eosinophil adhesion t o VCAM-1 was enhanced by 8A2, but adhesion to fibronectin could only h e detected in the presence of 8A2. Concentrations of 8A2 that were app roximately 100-fold less than saturating induced maximal eosinophil ad hesion, Adhesion to VCAM-1 in the presence of 8A2 was effectively inhi bited by alpha(4) and beta(1) integrin mAbs; beta(7) mAb had partial i nhibitory activity, Connecting segment-1 peptide and alpha(4) mAb bloc ked 8A2-dependent fibronectin binding; beta(1), beta(2), and beta(7) i ntegrin mAbs had partial inhibitory activity, Eosinophils obtained fro m bronchoalveolar lavage fluids and blood eosinophils stimulated with IL-5, platelet-activating factor, or RANTES displayed increased beta(2 ) integrin-dependent. not alpha(4) integrin-dependent, attachment. Spo ntaneous adhesion of eosinophils to VCAM-1 was significantly reduced b y the tyrosine kinase inhibitor tyrphostin B46 (inhibitory concentrati on of 50% congruent to 20 mu mol/L); this effect was reversed by 8A2. Conclusions: The functional activity of integrins on eosinophils can b e positively and negatively regulated. Altered integrin avidity may in fluence eosinophil recruitment in vivo.