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Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 2976-2983
Molecular Mechanisms of Zinc-Dependent Leukocyte Adhesion Involving
the Urokinase Receptor and  2-Integrins
Triantafyllos Chavakis,
Andreas E. May,
Klaus T. Preissner, and
Sandip M. Kanse
From the Haemostasis Research Unit, Kerckhoff-Klinik, MPI, Bad
Nauheim; and the Medizinische Klinik und Deutsches Herzzentrum,
Technische Universität München, Munich, Germany.
The trace element Zinc (Zn2+) has been implicated as a
mediator in host defense, yet the molecular basis for its extracellular functions remains obscure. Here, we demonstrate that Zn2+
can induce the adhesion of myelomonocytic cells to the endothelium, as
well as to the provisional matrix proteins vitronectin (VN) and
fibrinogen (FBG), which are pivotal steps for the recruitment of
leukocytes into inflamed/injured tissue. Physiologic concentrations of
Zn2+ increased the urokinase receptor (uPAR)-mediated
adhesion of myelomonocytic cells to VN, whereas other divalent cations
had smaller effects. Zn2+-induced cell adhesion to VN was
abolished by cation chelators such as 1-10-phenanthroline, as well as
by plasminogen activator inhibitor-1 (PAI-1) and a monoclonal antibody
(MoAb) against uPAR. These characteristics could be recapitulated with
a uPAR-transfected cell line emphasizing the specificity of this
receptor system for Zn2+-dependent cell adhesion. Like
urokinase (uPA), Zn2+ increased the binding of
radiolabeled VN to uPAR-expressing cells, as well as the interaction of
VN with immobilized uPAR in an isolated system. Moreover,
Zn2+ enhanced leukocytic cell adhesion to FBG and
endothelial cell monolayers by activating  2-integrins.
Instead of the direct 2-integrin activation through the
divalent cation binding site, Zn2+-induced integrin
activation was mediated via uPAR, a crucial regulator of this system.
The present study uncovers for the first time
Zn2+-mediated cell adhesion mechanisms that may play a
crucial role in modulating leukocyte adhesion to vessel wall components.
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