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

Leus, N. G. J., van den Bosch, T., van der Wouden, P. E., Krist, K., Ourailidou, M. E., Eleftheriadis, N., Kistemaker, L. E. M., Bos, S., Gjaltema, R. A. F., Mekonnen, S. A., Bischoff, R., Gosens, R., Haisma, H. J. & Dekker, F. J., 27-Mar-2017, In : Scientific Reports. 7, 18 p., 45047.

Research output: Contribution to journalArticleAcademicpeer-review

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-kappa B, among others. NF-kappa B is regulated by lysine acetylation; a post-translational modification installed by histone acetyltransferases and removed by histone deacetylases (HDACs). We hypothesized that small molecule HDAC inhibitors (HDACi) targeting class I HDACs members that can regulate NF-kappa B could attenuate inflammatory responses in COPD via modulation of the NF-kappa B signaling output. MS-275 is an isoform-selective inhibitor of HDAC1-3. In precision-cut lung slices and RAW264.7 macrophages, MS-275 upregulated the expression of both pro-and anti-inflammatory genes, implying mixed effects. Interestingly, anti-inflammatory IL10 expression was upregulated in these model systems. In the macrophages, this was associated with increased NF-kappa B activity, acetylation, nuclear translocation, and binding to the IL10 promoter. Importantly, in an in vivo model of cigarette smoke-exposed C57Bl/6 mice, MS-275 robustly attenuated inflammatory expression of KC and neutrophil influx in the lungs. This study highlights for the first time the potential of isoform-selective HDACi for the treatment of inflammatory lung diseases like COPD.

Original languageEnglish
Article number45047
Number of pages18
JournalScientific Reports
Volume7
Publication statusPublished - 27-Mar-2017

    Keywords

  • OBSTRUCTIVE PULMONARY-DISEASE, NF-KAPPA-B, HISTONE DEACETYLASE INHIBITORS, CUT LUNG SLICES, GENE-EXPRESSION, ANTIINFLAMMATORY PROPERTIES, INHALED CORTICOSTEROIDS, MEDIATED INFLAMMATION, IN-VITRO, EX-VIVO

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