Journal
FEBS LETTERS
Volume 581, Issue 7, Pages 1317-1322Publisher
WILEY
DOI: 10.1016/j.febslet.2007.02.045
Keywords
cytotoxicity; NK cells; histone deacetylase inhibitors; NK cell activating and inhibitory receptors; nuclear factor kappa B
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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. NF kappa B activation in IL-2-activated NK cells was inhibited by both HDACi. Pharmacologic inhibition of NF kappa B 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 NF kappa B activation. (c) 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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