Histone deacetylase inhibitors suppress natural killer cell cytolytic activity.
Treatment of transformed cells from leukemia or solid tumors with histone deacetylase inhibitors (HDACi) was shown to increase their sensitivity to NK cell lysis. In this study, treatment of IL-2-activated NK cells with HDACi including suberoylanilide hydroxamic acid and valproic acid was studied. Both drugs at therapeutic concentrations inhibited NK cell cytotoxicity on human leukemic cells. This inhibition was associated with decreased expression and function of NK cell activating receptors NKp46 and NKp30 as well as impaired granule exocytosis. NFkappaB activation in IL-2-activated NK cells was inhibited by both HDACi. Pharmacologic inhibition of NFkappaB activity resulted in similar effects on NK cell activity like those observed for HDACi. These results demonstrate for the first time that HDACi prevent NK cytotoxicity by downregulation of NK cell activating receptors probably through the inhibition of NFkappaB activation.
Ogbomo
Henry
H
Institut für Medizinische Virologie, Zentrum der Hygiene, Klinikum der Johann Wolfgang Goethe-Universität, Paul-Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany.
Michaelis
Martin
M
Kreuter
Jörg
J
Doerr
Hans Wilhelm
HW
Cinatl
Jindrich
J
D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D055627:Natural Cytotoxicity Triggering Receptor 1; D055628:Natural Cytotoxicity Triggering Receptor 3; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000276:immunology; D014635:Valproic Acid / Q000494:pharmacology; D000077337:Vorinostat
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007376:Interleukin-2; C112260:NCR1 protein, human; C431710:NCR3 protein, human; D016328:NF-kappa B; D055627:Natural Cytotoxicity Triggering Receptor 1; D055628:Natural Cytotoxicity Triggering Receptor 3; D011971:Receptors, Immunologic; D000077337:Vorinostat; D014635:Valproic Acid