title: The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-κB.
abstract: Histone 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-κB p65 and its deacetylation at various lysines. NF-κB 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-κB 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.
authors.affiliation: Rudolf-Buchheim-Institute of Pharmacology, Institute of Biochemistry, Justus-Liebig-University Giessen, D-35392 Giessen, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ziesché
authors.forename: Daniela
authors.initials: D
authors.lastname: Kettner-Buhrow
authors.forename: Axel
authors.initials: A
authors.lastname: Weber
authors.forename: Tobias
authors.initials: T
authors.lastname: Wittwer
authors.forename: Liane
authors.initials: L
authors.lastname: Jurida
authors.forename: Johanna
authors.initials: J
authors.lastname: Soelch
authors.forename: Helmut
authors.initials: H
authors.lastname: Müller
authors.forename: Doris
authors.initials: D
authors.lastname: Newel
authors.forename: Petra
authors.initials: P
authors.lastname: Kronich
authors.forename: Heike
authors.initials: H
authors.lastname: Schneider
authors.forename: Oliver
authors.initials: O
authors.lastname: Dittrich-Breiholz
authors.forename: Srividya
authors.initials: S
authors.lastname: Bhaskara
authors.forename: Scott W
authors.initials: SW
authors.lastname: Hiebert
authors.forename: Michael O
authors.initials: MO
authors.lastname: Hottiger
authors.forename: Haiying
authors.initials: H
authors.lastname: Li
authors.forename: Ezra
authors.initials: E
authors.lastname: Burstein
authors.forename: M Lienhard
authors.initials: ML
authors.lastname: Schmitz
authors.forename: Michael
authors.initials: M
authors.lastname: Kracht
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000502:physiology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D012319:RNA Polymerase II / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D000099186:Histone Deacetylase 3
chemical_list: D054426:Chemokine CXCL2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D007375:Interleukin-1; D016209:Interleukin-8; D016328:NF-kappa B; D012319:RNA Polymerase II; D051996:Transcription Factor RelA; D000099186:Histone Deacetylase 3; C404915:Cxcl2 protein, mouse; C012589:trichostatin A