UROKINASE RECEPTOR (CD87) REGULATES LEUKOCYTE RECRUITMENT VIA BETA(2)INTEGRINS IN-VIVO

The urokinase receptor (CD87; uPAR) is found in close association with beta(2) integrins on leukocytes. We studied the functional consequenc e of this association for leukocyte adhesion and migration. In vivo, t he beta(2) integrin-dependent recruitment of leukocytes to the inflame d peritoneum of uPAR-deficient mice was significantly reduced as compa red with wild-type animals. In vitro, beta(2) integrin-mediated adhesi on ofleukocytes to endothelium was lost upon removal of uPAR from the leukocyte surface by phosphatidyl-inositol-specific phospholipase C. L eukocyte adhesion was reconstituted when soluble intact uPAR, but not a truncated form lacking the uPA-binding domain, was allowed to reasso ciate with the cell surface, uPAR ligation with a monoclonal antibody induced adhesion of monocytic cells and neutrophils to vascular endoth elium by six- to eightfold, whereas ligation with inactivated uPA sign ificantly reduced cell-to-cell adhesion irrespective of the beta(2) in tegrin-stimulating pathway. These data indicate that beta(2) integrin- mediated leukocyte-endothelial cell interactions and recruitment to in flamed areas require the presence of uPAR and define a new phenotype f or uPAR-deficient mice. Moreover, uPAR ligation differentially modulat es leukocyte adhesion to endothelium and provides novel targets for th erapeutic strategies in inflammation-related vascular pathologies.