Abstract
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.
Highlights
Periodontitis is an inflammatory disease of the periodontium caused by microbial imbalance and the anaerobic bacterium Porphyromonas gingivalis plays a central role in driving the chronic inflammation [1]
We initiated this study by investigating whether bromodomain and extraterminal domain (BET) bromodomain proteins are involved in gingival fibroblasts (GFs) inflammatory activation in response to cytokines that are present in the inflamed gingival tissue
BET inhibition significantly suppressed cytokine-induced mRNA expression of a broad range of inflammatory mediators involved in the pathogenesis of periodontitis, including IL8, IL1B, CCL2, CCL5, MMP3, and COX2 (Figure 1A)
Summary
Periodontitis is an inflammatory disease of the periodontium caused by microbial imbalance (dysbiosis) and the anaerobic bacterium Porphyromonas gingivalis plays a central role in driving the chronic inflammation [1]. Resident cells of the gingival tissue, including gingival epithelial cells (GECs) and gingival fibroblasts (GFs), represent the first line of defense against oral pathogens and are considered an important component of the innate immune system [3, 4]. Their chronic activation due to persistent interaction with oral bacteria, which involves the secretion of large quantities of cytokines, chemokines, matrixdegrading enzymes, and prostaglandins, significantly contributes to periodontitis pathogenesis [5]. Expression of inflammatory mediators is tightly regulated by epigenetic mechanisms, among which reversible acetylation of histone proteins plays a critical role. BET proteins have emerged as potential therapeutic targets, and compounds targeting their tandem bromodomains are currently being evaluated in clinical trials [12]
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