Molecular mechanisms of zinc-dependent leukocyte adhesion involving the urokinase receptor and beta(2)-integrins

The trace element Zinc (Zn2+) has been implicated as a mediator in host def ense, yet the molecular basis for its extracellular functions remains obscu re. Here, we demonstrate that Zn2+ can induce the adhesion of myelomonocyti c cells to the endothelium, as well as to the provisional matrix proteins v itronectin (VN) and fibrinogen (FBG), which are pivotal steps for the recru itment of leukocytes into inflamed/injured tissue. Physiologic concentratio ns of Zn2+ increased the urokinase receptor (uPAR)-mediated adhesion of mye lomonocytic cells to VN, whereas other divalent cations had smaller effects . Zn2+-induced cell adhesion to VN was abolished by cation chelators such a s 1-10-phenanthroline, as well as by plasminogen activator inhibitor-1 (PAI -1) and a monoclonal antibody (MoAb) against uPAR. These characteristics co uld be recapitulated with a uPAR-transfected cell line emphasizing the spec ificity of this receptor system for Zn2+-dependent cell adhesion. Like urok inase (uPA), Zn2+ increased the binding of radiolabeled VN to uPAR-expressi ng cells, as well as the interaction of VN with immobilized uPAR in an isol ated system. Moreover, Zn2+ enhanced leukocytic cell adhesion to FBG and en dothelial cell monolayers by activating beta(2)-integrins. Instead of the d irect beta(2)-integrin activation through the divalent cation binding site, Zn2+-induced integrin activation was mediated via uPAR, a crucial regulato r of this system. The present study uncovers for the first time Zn2+-mediat ed cell adhesion mechanisms that may play a crucial role in modulating leuk ocyte adhesion to vessel wall components. (C) 1999 by The American Society of Hematology.