Epigenetic histone modulation contributes to improvements in inflammatory bowel disease via EBI3
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
Epigenetic histone modulation contributes to improvements in inflammatory bowel disease via EBI3 Alexandra Wetzel1 · Bettina Scholtka1 · Christian Gerecke1 · Burkhard Kleuser1 Received: 21 August 2019 / Revised: 10 December 2019 / Accepted: 2 January 2020 © The Author(s) 2020
Abstract Ulcerative colitis (UC) is characterized by relapsing–remitting inflammatory episodes paralleled by varying cytokine levels, suggesting that switching epigenetic processes might be involved. However, the epigenetic impact on cytokine levels in colitis is mostly unexplored. The heterodimeric interleukin (IL)-12 cytokine family have various functions in both pro- and antiinflammatory processes. The family member IL-35 (EBI3/IL-12p35) was recently reported to play an anti-inflammatory role in UC. Therefore, we aimed to investigate a possible epigenetic regulation of the IL-35 subunits in vitro and in vivo, and to examine the epigenetic targeting of EBI3 expression as a therapeutic option for UC. Exposure to either the pro-inflammatory TNFα or to histone deacetylase inhibitors (HDACi) significantly increased EBI3 expression in Human Colon Epithelial Cells (HCEC) generated from healthy tissue. When applied in combination, a drastic upregulation of EBI3 expression occurred, suggesting a synergistic mechanism. Consequently, IL-35 was increased as well. In vivo, the intestines of HDACi-treated wild-type mice exhibited reduced pathological signs of colitis compared to non-treated colitic mice. However, the improvement by HDACi treatment was completely lost in Ebi3-deficient mice (Ebi3−/−). In fact, HDACi appeared to exacerbate the disease phenotype in Ebi3−/−. In conclusion, our results reveal that under inflammatory conditions, EBI3 is upregulated by the epigenetic mechanism of histone acetylation. The in vivo data show that the deficiency of EBI3 plays a key role in colitis manifestation. Concordantly, our data suggest that conditions promoting histone acetylation, such as upon HDACi application, improve colitis by a mechanism involving the local formation of the anti-inflammatory cytokine IL-35. Keywords Histone deacetylase inhibitor · Inhibitory cytokines · Interleukin-35 · SAHA · Ulcerative colitis Abbreviations Bcl-2 B-cell lymphoma-2 Bcl-xL B-cell lymphoma-extra large DMEM Dulbecco’s modified eagle’s medium DMSO Dimethyl sulfoxide DSS Dextran sulfate sodium Ebi3 Epstein–Barr virus-induced gene 3 HCEC Human Colon Epithelial Cells Alexandra Wetzel and Bettina Scholtka have contributed equally to the study. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-020-03451-9) contains supplementary material, which is available to authorized users. * Burkhard Kleuser kleuser@uni‑potsdam.de 1
Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur‑Scheunert‑Allee 114‑116, 14558 Nuthetal, Germany
HDAC Histone deacetylase HDACi Histone deacetylase inhibitor HMBS Hydroxymethylbila
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