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

Autor: Trees Jansen, Rab K. Prinjha, Anaísa V Ferreira, Rebecca C. Furze, Nicholas Smithers, Mihai G. Netea, Jorge Domínguez-Andrés
Rok vydání: 2019
Předmět:
0301 basic medicine
Neutrophils
Short Communication
Interleukin-1beta
Primary Cell Culture
Immunology
Immunity to infection
lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4]
chemical and pharmacologic phenomena
Inflammation
Biology
Heterocyclic Compounds
4 or More Rings
Monocytes
Proinflammatory cytokine
BET inhibitor
Interferon-gamma
03 medical and health sciences
0302 clinical medicine
Immune system
All institutes and research themes of the Radboud University Medical Center
Immunity
Candida albicans
medicine
Humans
Immunologic Factors
Immunology and Allergy
Basic
Innate immune system
Interleukin-6
Tumor Necrosis Factor-alpha
Aspergillus fumigatus
Interleukins
Interleukin-17
I‐BET151
biology.organism_classification
Endocytosis
Interleukin-10
Bromodomain
Short Communication|Basic
030104 developmental biology
Gene Expression Regulation
Host-Pathogen Interactions
medicine.symptom
Signal Transduction
030215 immunology
Zdroj: European Journal of Immunology, 49, 2044-2050
European Journal of Immunology, 49, 11, pp. 2044-2050
European Journal of Immunology
ISSN: 0014-2980
DOI: 10.1002/eji.201848081
Popis: 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.
Treatment of immune cells with the clinically relevant small molecular histone mimic BET inhibitor I‐BET151 allows the modulation of immune responses during fungal–immune interaction through the reprogramming of the epigenetic landscape of the cells, decreasing the production of pro‐inflammatory cytokines and inhibiting the induction of trained immunity.
Databáze: OpenAIRE
Externí odkaz: