title: Histone deacetylase inhibitors block nuclear factor-κB-dependent transcription by interfering with RNA polymerase II recruitment.
abstract: Histone deacetylase inhibitors (HDACi) have been shown to exhibit anti-inflammatory activity, but their mechanism of action is poorly understood. Trichostatin A (TSA) and the cyclic tetrapeptide class inhibitor Ky-2 inhibit both lipopolysaccharide-induced tumor necrosis factor-α (TNF-α) production in rats and TNF-α-induced expression of inflammatory genes in HeLa cells. We assessed the molecular mechanism underlying TSA-induced anti-inflammatory activity by genetically dissecting activation of the nuclear factor-κB (NF-κB) pathway following stimulation with TNF-α. Trichostatin A did not inhibit degradation of IκBα, nuclear translocation and DNA binding of NF-κB; also, the drug did not affect transient expression from exogenous κB-reporter plasmids. However, endogenous expression of inflammatory cytokines such as interleukin-8 (IL-8) was greatly reduced, even in the absence of de novo protein synthesis, suggesting that HDACi directly inhibits NF-κB-induced transcription. Indeed, chromatin immunoprecipitation (ChIP) analysis showed that events related to transcriptional activation of the IL-8 gene region in response to TNF-α, including recruitment of RNA polymerase II (Pol II), were compromised in the presence of TSA. These data indicate that HDAC activity is required for the efficient initiation and/or elongation of inflammatory gene transcription mediated by NF-κB.
authors.affiliation: Chemical Genetics Laboratory/Chemical Genomics Research Group, RIKEN Advanced Science Institute, Saitama, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Furumai
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ito
authors.forename: Kenji
authors.initials: K
authors.lastname: Ogawa
authors.forename: Satoko
authors.initials: S
authors.lastname: Maeda
authors.forename: Akiko
authors.initials: A
authors.lastname: Saito
authors.forename: Norikazu
authors.initials: N
authors.lastname: Nishino
authors.forename: Sueharu
authors.initials: S
authors.lastname: Horinouchi
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects*; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism*; D016328:NF-kappa B / Q000096:biosynthesis*; D012319:RNA Polymerase II / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016328:NF-kappa B; C012589:trichostatin A; D012319:RNA Polymerase II