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Eur J Immunol. 2019 Jun 17. doi: 10.1002/eji.201848081. [Epub ahead of print]

Bromodomain inhibitor I-BET151 suppresses immune responses during fungal-immune interaction.

Author information

1
Department of Internal Medicine and Radboud Center for Infectious diseases (RCI), Radboud University Nijmegen Medical Centre, 6500HB, Nijmegen, the Netherlands.
2
Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, 4050-313, Porto, Portugal.
3
Epigenetics DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Medicines Research Centre, Stevenage, SG1 2NY, UK.
4
Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115, Bonn, Germany.
5
Human Genomics Laboratory, Craiova University of Medicine and Pharmacy, Craiova, Romania.

Abstract

Changes in the epigenetic landscape of immune cells are a crucial component of gene activation during the induction of inflammatory responses, therefore it has been hypothesized that epigenetic modulation could be employed to restore homeostasis in inflammatory scenarios. Fungal pathogens cause a large burden of morbidity and even mortality due to the hyperinflammatory processes that induce mucosal, allergic or systemic infections. Bromodomain and extraterminal domain (BET) proteins are considered as one as the most tantalizing pharmacological targets for the modulation of inflammatory responses at the epigenetic level. Nothing is known of the role of BET inhibitors on the inflammation induced by fungal pathogens. In the present study, we assessed the in vitro efficacy of the small molecular histone mimic BET inhibitor I-BET151 to modulate innate immune responses during fungal-immune interaction with the clinically relevant fungal pathogens Candida albicans and Aspergillus fumigatus. Our results prove that BET inhibitors (I-BETs) represent an important modulator of inflammation induced by fungal pathogens: both direct production of proinflammatory cytokines and the induction of trained immunity were inhibited by I-BET151. These modulatory effects are likely to have important potential implications in clinically relevant situations.

KEYWORDS:

Aspergillus fumigatus; Candida albicans; I-BET151; monocytes; neutrophils

PMID:
31206650
DOI:
10.1002/eji.201848081

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