Molecular mechanisms of zinc-dependent leukocyte adhesion involving the urokinase receptor and beta2-integrins.
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 beta2-integrins. Instead of the direct beta2-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.
Chavakis
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Haemostasis Research Unit, Kerckhoff-Klinik, MPI, Bad Nauheim, Medizinische Klinik und Deutsches Herzzentrum, Technische Universität München, Munich, Germany.
May
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AE
Preissner
K T
KT
Kanse
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SM
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018821:CD18 Antigens / Q000502:physiology*; D002413:Cations, Divalent / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D003035:Cobalt / Q000494:pharmacology; D003300:Copper / Q000494:pharmacology; D005340:Fibrinogen / Q000502:physiology; D006801:Humans; D007700:Kinetics; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D008345:Manganese / Q000494:pharmacology; D009532:Nickel / Q000494:pharmacology; D010618:Phenanthrolines / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000502:physiology*; D055293:Receptors, Urokinase Plasminogen Activator; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D020298:U937 Cells; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism / Q000494:pharmacology; D019096:Vitronectin / Q000502:physiology*; D015032:Zinc / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D018821:CD18 Antigens; D002413:Cations, Divalent; D002614:Chelating Agents; C524898:PLAUR protein, human; D010618:Phenanthrolines; D017395:Plasminogen Activator Inhibitor 1; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D019096:Vitronectin; D003035:Cobalt; D008345:Manganese; D003300:Copper; D009532:Nickel; D005340:Fibrinogen; D014568:Urokinase-Type Plasminogen Activator; D015032:Zinc; D013755:Tetradecanoylphorbol Acetate; C025205:1,10-phenanthroline