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.

Class I HDACs Affect DNA Replication, Repair, and Chromatin Structure: Implications for Cancer Therapy

“…Consistent with these findings, in vitro stimulation of Hdac3 -/ -macrophages revealed a significantly impaired induction of pro-inflammatory transcriptional programs, which was associated with an impaired INF-b response (20). Finally, HDAC3 contributed to induction of inflammatory gene expression after IL-1 stimulation through its ability to remove inhibitory acetylation marks on NF-jB (135). These results are again consistent with the idea that inhibition of HDAC3 mediates the anti-inflammatory effects of broadspectrum HDIs which are already in the clinic.…”

Histone acetyltransferases are crucial regulators in NF-κB mediated inflammation

“…A noteworthy recent study reports that HDAC3 deacetylates p65 on lysines 122, 123, 314 and 315, and that it is a positive regulator of inflammatory gene expression [64], which might seem contradictory to the previously mentioned initial studies [6,57] and studies using MS275 [58,61,62]. However, note that these concern not only HDAC3 but also HDAC1 and 2.…”

Suppression of monosodium urate crystal-induced cytokine production by butyrate is mediated by the inhibition of class I histone deacetylases

“…Both HDAC1 and HDAC2 have been described to suppress NF-κB signalling 27–29. For HDAC3, both inhibitory30 and stimulatory31 32 effects on NF-κB signalling have been described. Next to direct deacetylation of NF-κB subunits, HDAC3 can also potentiate NF-κB activation through repression of nuclear receptors such as peroxisome proliferator-activated receptor γ,33 which has been implicated as a mechanism in the anti-inflammatory effects of butyrate 34–36…”