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BET Bromodomain Inhibitors Suppress Inflammatory Activation of Gingival Fibroblasts and Epithelial Cells From Periodontitis Patients

BET bromodomain proteins are important epigenetic regulators of gene expression that bind acetylated histone tails and regulate the formation of acetylation-dependent chromatin complexes. BET inhibitors suppress inflammatory responses in multiple cell types and animal models, and protect against bon...

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Autores principales: Maksylewicz, Anna, Bysiek, Agnieszka, Lagosz, Katarzyna B., Macina, Justyna M., Kantorowicz, Malgorzata, Bereta, Grzegorz, Sochalska, Maja, Gawron, Katarzyna, Chomyszyn-Gajewska, Maria, Potempa, Jan, Grabiec, Aleksander M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503739/
https://www.ncbi.nlm.nih.gov/pubmed/31114581
http://dx.doi.org/10.3389/fimmu.2019.00933
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author Maksylewicz, Anna
Bysiek, Agnieszka
Lagosz, Katarzyna B.
Macina, Justyna M.
Kantorowicz, Malgorzata
Bereta, Grzegorz
Sochalska, Maja
Gawron, Katarzyna
Chomyszyn-Gajewska, Maria
Potempa, Jan
Grabiec, Aleksander M.
author_facet Maksylewicz, Anna
Bysiek, Agnieszka
Lagosz, Katarzyna B.
Macina, Justyna M.
Kantorowicz, Malgorzata
Bereta, Grzegorz
Sochalska, Maja
Gawron, Katarzyna
Chomyszyn-Gajewska, Maria
Potempa, Jan
Grabiec, Aleksander M.
author_sort Maksylewicz, Anna
collection PubMed
description BET bromodomain proteins are important epigenetic regulators of gene expression that bind acetylated histone tails and regulate the formation of acetylation-dependent chromatin complexes. BET inhibitors suppress inflammatory responses in multiple cell types and animal models, and protect against bone loss in experimental periodontitis in mice. Here, we analyzed the role of BET proteins in inflammatory activation of gingival fibroblasts (GFs) and gingival epithelial cells (GECs). We show that the BET inhibitors I-BET151 and JQ1 significantly reduced expression and/or production of distinct, but overlapping, profiles of cytokine-inducible mediators of inflammation and bone resorption in GFs from healthy donors (IL6, IL8, IL1B, CCL2, CCL5, COX2, and MMP3) and the GEC line TIGK (IL6, IL8, IL1B, CXCL10, MMP9) without affecting cell viability. Activation of mitogen-activated protein kinase and nuclear factor-κB pathways was unaffected by I-BET151, as was the histone acetylation status, and new protein synthesis was not required for the anti-inflammatory effects of BET inhibition. I-BET151 and JQ1 also suppressed expression of inflammatory cytokines, chemokines, and osteoclastogenic mediators in GFs and TIGKs infected with the key periodontal pathogen Porphyromonas gingivalis. Notably, P. gingivalis internalization and intracellular survival in GFs and TIGKs remained unaffected by BET inhibitors. Finally, inhibition of BET proteins significantly reduced P. gingivalis-induced inflammatory mediator expression in GECs and GFs from patients with periodontitis. Our results demonstrate that BET inhibitors may block the excessive inflammatory mediator production by resident cells of the gingival tissue and identify the BET family of epigenetic reader proteins as a potential therapeutic target in the treatment of periodontal disease.
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spelling pubmed-65037392019-05-21 BET Bromodomain Inhibitors Suppress Inflammatory Activation of Gingival Fibroblasts and Epithelial Cells From Periodontitis Patients Maksylewicz, Anna Bysiek, Agnieszka Lagosz, Katarzyna B. Macina, Justyna M. Kantorowicz, Malgorzata Bereta, Grzegorz Sochalska, Maja Gawron, Katarzyna Chomyszyn-Gajewska, Maria Potempa, Jan Grabiec, Aleksander M. Front Immunol Immunology BET bromodomain proteins are important epigenetic regulators of gene expression that bind acetylated histone tails and regulate the formation of acetylation-dependent chromatin complexes. BET inhibitors suppress inflammatory responses in multiple cell types and animal models, and protect against bone loss in experimental periodontitis in mice. Here, we analyzed the role of BET proteins in inflammatory activation of gingival fibroblasts (GFs) and gingival epithelial cells (GECs). We show that the BET inhibitors I-BET151 and JQ1 significantly reduced expression and/or production of distinct, but overlapping, profiles of cytokine-inducible mediators of inflammation and bone resorption in GFs from healthy donors (IL6, IL8, IL1B, CCL2, CCL5, COX2, and MMP3) and the GEC line TIGK (IL6, IL8, IL1B, CXCL10, MMP9) without affecting cell viability. Activation of mitogen-activated protein kinase and nuclear factor-κB pathways was unaffected by I-BET151, as was the histone acetylation status, and new protein synthesis was not required for the anti-inflammatory effects of BET inhibition. I-BET151 and JQ1 also suppressed expression of inflammatory cytokines, chemokines, and osteoclastogenic mediators in GFs and TIGKs infected with the key periodontal pathogen Porphyromonas gingivalis. Notably, P. gingivalis internalization and intracellular survival in GFs and TIGKs remained unaffected by BET inhibitors. Finally, inhibition of BET proteins significantly reduced P. gingivalis-induced inflammatory mediator expression in GECs and GFs from patients with periodontitis. Our results demonstrate that BET inhibitors may block the excessive inflammatory mediator production by resident cells of the gingival tissue and identify the BET family of epigenetic reader proteins as a potential therapeutic target in the treatment of periodontal disease. Frontiers Media S.A. 2019-04-30 /pmc/articles/PMC6503739/ /pubmed/31114581 http://dx.doi.org/10.3389/fimmu.2019.00933 Text en Copyright © 2019 Maksylewicz, Bysiek, Lagosz, Macina, Kantorowicz, Bereta, Sochalska, Gawron, Chomyszyn-Gajewska, Potempa and Grabiec. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Maksylewicz, Anna
Bysiek, Agnieszka
Lagosz, Katarzyna B.
Macina, Justyna M.
Kantorowicz, Malgorzata
Bereta, Grzegorz
Sochalska, Maja
Gawron, Katarzyna
Chomyszyn-Gajewska, Maria
Potempa, Jan
Grabiec, Aleksander M.
BET Bromodomain Inhibitors Suppress Inflammatory Activation of Gingival Fibroblasts and Epithelial Cells From Periodontitis Patients
title BET Bromodomain Inhibitors Suppress Inflammatory Activation of Gingival Fibroblasts and Epithelial Cells From Periodontitis Patients
title_full BET Bromodomain Inhibitors Suppress Inflammatory Activation of Gingival Fibroblasts and Epithelial Cells From Periodontitis Patients
title_fullStr BET Bromodomain Inhibitors Suppress Inflammatory Activation of Gingival Fibroblasts and Epithelial Cells From Periodontitis Patients
title_full_unstemmed BET Bromodomain Inhibitors Suppress Inflammatory Activation of Gingival Fibroblasts and Epithelial Cells From Periodontitis Patients
title_short BET Bromodomain Inhibitors Suppress Inflammatory Activation of Gingival Fibroblasts and Epithelial Cells From Periodontitis Patients
title_sort bet bromodomain inhibitors suppress inflammatory activation of gingival fibroblasts and epithelial cells from periodontitis patients
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503739/
https://www.ncbi.nlm.nih.gov/pubmed/31114581
http://dx.doi.org/10.3389/fimmu.2019.00933
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