Histone deacetylase inhibitors suppress natural killer cell cytolytic activity |
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Authors: | Ogbomo Henry Michaelis Martin Kreuter Jörg Doerr Hans Wilhelm Cinatl Jindrich |
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Affiliation: | Institut für Medizinische Virologie, Zentrum der Hygiene, Klinikum der Johann Wolfgang Goethe-Universit?t, Paul-Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany. |
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Abstract: | 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. |
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Keywords: | CT, threshold cycles DNAM-1, DNAX accessory molecule-1 FCS, fetal calf serum HDACi, histone deacetylase inhibitors IL-2, interleukin-2 IMDM, Iscove’s modified Dulbecco’s medium KIR, killer immunoglobulin-like receptors LFA-1, lymphocyte function antigen-1 mAb, monoclonal antibody MICA/B, MHC class I-related chain A/B NCR, natural cytotoxic receptors NFκB, Nuclear factor kappa B NK, natural killer NKG2A, NK group 2, member A NKG2D, NK group 2, member D PE, phycoerythrin RFU, relative fluorescent units SAHA, suberoylanilide hydroxamic acid VPA, valproic acid |
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