Abstract
Inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, commonly referred to as statins, are inhibitors of cholesterol biosynthesis. They are broadly used for treating hypercholesterolemia and for prevention of cardio- and cerebrovascular diseases. Recent publications show that statins also act as immunomodulatory drugs. Here, we show that lipophilic statins inhibit NK-cell degranulation and cytotoxicity. This effect was reversible by addition of substrates of isoprenylation, but not by addition of cholesterol. In NK-target cell conjugates intracellular Ca(2+) flux was unaffected by statin treatment. However, statins strongly reduced the amount of conjugate formation between NK and target cells. This inhibition was paralleled by a statin-dependent inhibition of LFA-1-mediated adhesion and a reduction of NK-cell polarization. This demonstrates that statins impair the formation of effector-target cell conjugates resulting in the disruption of early signaling and the loss of NK-cell cytotoxicity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Calcium Signaling / drug effects
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Cell Adhesion / drug effects*
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Cell Adhesion / immunology
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Cell Communication / drug effects*
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Cell Communication / immunology
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Cell Degranulation / drug effects
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Cell Degranulation / immunology
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Cell Line, Tumor
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Cell Polarity / drug effects
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Cytotoxicity, Immunologic / drug effects*
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
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Intercellular Adhesion Molecule-1 / metabolism
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K562 Cells
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Killer Cells, Natural / cytology
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Killer Cells, Natural / drug effects*
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Killer Cells, Natural / immunology
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Killer Cells, Natural / metabolism
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Lymphocyte Function-Associated Antigen-1 / metabolism*
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Mevalonic Acid / pharmacology
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Phospholipase C gamma / metabolism
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Phosphorylation / drug effects
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Polyisoprenyl Phosphates / pharmacology
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Prenylation / drug effects
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Protein Binding / drug effects
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Receptors, Natural Killer Cell / metabolism
Substances
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Lymphocyte Function-Associated Antigen-1
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Polyisoprenyl Phosphates
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Receptors, Natural Killer Cell
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Intercellular Adhesion Molecule-1
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Phospholipase C gamma
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geranylgeranyl pyrophosphate
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Mevalonic Acid