Ziesché, ElisabethElisabethZieschéKettner-Buhrow, DanielaDanielaKettner-BuhrowWeber, AxelAxelWeberWittwer, TobiasTobiasWittwerJurida, LianeLianeJuridaSoelch, JohannaJohannaSoelchMüller, HelmutHelmutMüllerNewel, DorisDorisNewelKronich, PetraPetraKronichSchneider, HeikeHeikeSchneiderDittrich-Breiholz, OliverOliverDittrich-BreiholzBhaskara, SrividyaSrividyaBhaskaraHiebert, Scott W.Scott W.HiebertHottiger, Michael O.Michael O.HottigerLi, HaiyingHaiyingLiBurstein, EzraEzraBursteinSchmitz, M. LienhardM. LienhardSchmitzKracht, MichaelMichaelKracht2022-11-182012-11-202022-11-182012http://nbn-resolving.de/urn:nbn:de:hebis:26-opus-90755https://jlupub.ub.uni-giessen.de/handle/jlupub/9664http://dx.doi.org/10.22029/jlupub-9052Histone deacetylase (HDAC) 3, as a cofactor in co-repressor complexes containing silencing mediator for retinoid or thyroid-hormone receptors (SMRT) and nuclear receptor co-repressor (N-CoR), has been shown to repress gene transcription in a variety of contexts. Here, we reveal a novel role for HDAC3 as a positive regulator of IL-1-induced gene expression. Various experimental approaches involving RNAi-mediated knockdown, conditional gene deletion or small molecule inhibitors indicate a positive role of HDAC3 for transcription of the majority of IL-1-induced human or murine genes. This effect was independent from the gene regulatory effects mediated by the broad-spectrum HDAC inhibitor trichostatin A (TSA) and thus suggests IL-1-specific functions for HDAC3. The stimulatory function of HDAC3 for inflammatory gene expression involves a mechanism that uses binding to NF-?B p65 and its deacetylation at various lysines. NF-?B p65-deficient cells stably reconstituted to express acetylation mimicking forms of p65 (p65 K/Q) had largely lost their potential to stimulate IL-1-triggered gene expression, implying that the co-activating property of HDAC3 involves the removal of inhibitory NF-?B p65 acetylations at K122, 123, 314 and 315. These data describe a novel function for HDAC3 as a co-activator in inflammatory signaling pathways and help to explain the anti-inflammatory effects frequently observed for HDAC inhibitors in (pre)clinical use.enNamensnennung - Nicht-kommerziell - Keine Bearbeitung 3.0 Internationalhistone deacetylase 3 (HDAC3)NF-kappaB p65positive gen-regulation of IL-1co-activator in inflammatory signaling pathwaysddc:610