Abstract
Class I and II histone deacetylases (HDAC) are considered important regulators of immunity and inflammation. Modulation of HDAC expression and activity is associated with altered inflammatory responses but reports are controversial and the specific impact of single HDACs is not clear. We examined class I and II HDACs in TLR-4 signaling pathways in murine macrophages with a focus on IκB kinase epsilon (IKKε) which has not been investigated in this context before. Therefore, we applied the pan-HDAC inhibitors (HDACi) trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) as well as HDAC-specific siRNA. Administration of HDACi reduced HDAC activity and decreased expression of IKKε although its acetylation was increased. Other pro-inflammatory genes (IL-1β, iNOS, TNFα) also decreased while COX-2 expression increased. HDAC 2, 3 and 4, respectively, might be involved in IKKε and iNOS downregulation with potential participation of NF-κB transcription factor inhibition. Suppression of HDAC 1–3, activation of NF-κB and RNA stabilization mechanisms might contribute to increased COX-2 expression. In conclusion, our results indicate that TSA and SAHA exert a number of histone- and HDAC-independent functions. Furthermore, the data show that different HDAC enzymes fulfill different functions in macrophages and might lead to both pro- and anti-inflammatory effects which have to be considered in therapeutic approaches.
Highlights
Histone proteins as carriers of DNA in eukaryotes are able to influence gene expression depending on several post-translational histone modifications such as phosphorylation, methylation and acetylation [1,2,3]
The data show that different histone deacetylases (HDAC) enzymes fulfill different functions in macrophages and might lead to both pro- and anti-inflammatory effects which have to be considered in therapeutic approaches
Histone acetylation by histone acetyltransferases (HATs) leads to relaxation of the chromatin structure which allows binding of transcription factors followed by increased gene expression
Summary
Histone proteins as carriers of DNA in eukaryotes are able to influence gene expression depending on several post-translational histone modifications such as phosphorylation, methylation and acetylation [1,2,3]. Histone modification is discussed as one major epigenetic modulation in the process of macrophage activation and polarization, but the specific role of histone acetylation in the context of inflammation and inflammatory macrophages is still far from being completely elucidated [11]. SAHA, known as Vorinostat, is approved in some countries for the treatment of cutaneous T-cell lymphoma and in clinical testing for other cancer types and HIV These compounds are discussed increasingly for their potential use in inflammatory diseases [12,13]. We investigated the impact of the HDACi on inflammatory gene expression with a focus on IKKε and used siRNAs against different HDACs to figure out which specific HDAC is involved in the differential target regulations
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