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Research article - Peer-reviewed, 2017

Inhibition of the BET family of epigenetic reader proteins: A novel principle for modulating gene expression in IgE-activated mast cells

Garcia-Faroldi, Gianni; Ronnberg, Elin; Grujic, Mirjana; Pejler, Gunnar;

Abstract

Introduction: The BET family of bromodomain-containing proteins constitute epigenetic readers that bind to acetylated lysine residues of core histones, thereby translating epigenetic histone marks to effects on gene expression. BET inhibitors are currently emerging as promising therapeutic agents for treatment of various pathological conditions. Here, we explored the potential of using BET inhibition to modulate IgE-mediated responses in mast cells.Methods: We assessed the effects of BET inhibitors PFI-1, I-BET151, and I-BET762 on responses downstream of mast cell activation through IgE receptor cross-linking.Results: BET inhibitors were neither toxic for mast cells (at doses up to 20M), nor did they prevent IgE-mediated mast cell degranulation. However, we found that BET inhibition, in particular by I-BET151, suppressed IL-6 gene expression and IL-6 protein release in response to IgE-mediated mast cell activation. This was observed in both bone marrow-derived mast cells (BMMCs) and in mature peritoneal-cell derived mast cells. Further analysis showed that BET inhibition also suppressed the expression of a number of additional genes of those that were upregulated by IgE receptor cross-linking, including IL-3, IL-7R, CCR1, and ADAMTS9. However, BET inhibition was selective, i.e., several genes that were upregulated by IgE receptor cross-linking were not affected by BET inhibitors.Conclusions: These findings suggest that BET inhibition can interfere with the upregulated expression of selected genes in mast cells activated by IgE receptor cross-linking. Further, our findings introduce the concept of utilizing epigenetic mechanisms for modulating mast cell function in the context of IgE-driven disease.

Keywords

BET proteins; epigenetics; IgE; IL-6; mast cells

Published in

Immunity, Inflammation and Disease

2017, volume: 5, number: 2, pages: 141-150
Publisher: WILEY

Authors' information

Garcia-Faroldi, Gianni
Uppsala University
Ronnberg, Elin
Uppsala University
Grujic, Mirjana
Uppsala University
Uppsala University
Swedish University of Agricultural Sciences, Department of Anatomy, Physiology and Biochemistry (AFB)

UKÄ Subject classification

Immunology in the medical area

Publication Identifiers

DOI: https://doi.org/10.1002/iid3.150

URI (permanent link to this page)

https://res.slu.se/id/publ/112495