HDAC1-3 inhibitor MS-275 enhances IL10 expression in RAW264.7 macrophages and reduces cigarette smoke-induced airway inflammation in mice

• DOI: 10.1038/srep45047
• Publication Date: 2017-03-27T09:00:44Z
• Authors: Niek G. J. Leus; Thea van den Bosch; Petra E. van der ...; Kim Krist; Maria E. Ourailidou; Nikolaos Elefther...; Loes E. M. Kistem...; Sophie Bos; Rutger A. F. Gjal...; Solomon A. Mekonnen; Rainer Bischoff; Reinoud Gosens; Hidde J. Haisma; Frank J. Dekker
• Keywords: HDAC1

Abstract Chronic obstructive pulmonary disease (COPD) constitutes a major health burden. Studying underlying molecular mechanisms could lead to new therapeutic targets. Macrophages are orchestrators of COPD, by releasing pro-inflammatory cytokines. This process relies on transcription factors such as NF-κB, among others. NF-κB is regulated lysine acetylation; post-translational modification installed histone acetyltransferases and removed deacetylases (HDACs). We hypothesized that small molecule HDAC inhibitors (HDACi) targeting class I HDACs members can regulate attenuate inflammatory responses in COPD via modulation the signaling output. MS-275 an isoform-selective inhibitor HDAC1-3. In precision-cut lung slices RAW264.7 macrophages, upregulated expression both pro- anti-inflammatory genes, implying mixed effects. Interestingly, IL10 was these model systems. this associated with increased activity, acetylation, nuclear translocation, binding promoter. Importantly, vivo cigarette smoke-exposed C57Bl/6 mice, robustly attenuated KC neutrophil influx lungs. study highlights for first time potential HDACi treatment diseases like COPD.