Statins inhibit NK-cell cytotoxicity by interfering with LFA-1-mediated conjugate formation.
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.
Institute for Immunology, University Heidelberg, Heidelberg, Germany.
Patrick C
PC
Raemer
Kristine
K
Kohl
Carsten
C
Watzl
D020013:Calcium Signaling / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects* / Q000276:immunology; D002450:Cell Communication / Q000187:drug effects* / Q000276:immunology; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D008798:Mevalonic Acid / Q000494:pharmacology; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D054876:Prenylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D055607:Receptors, Natural Killer Cell / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016169:Lymphocyte Function-Associated Antigen-1; D011106:Polyisoprenyl Phosphates; D055607:Receptors, Natural Killer Cell; D018799:Intercellular Adhesion Molecule-1; D051966:Phospholipase C gamma; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid