Bromodomain and extra-terminal domain bromodomain inhibition prevents synovial inflammation via blocking IκB kinase–dependent NF-κB activation in rheumatoid fibroblast-like synoviocytes

Xiao, Youjun; Liang, Liuqin; Huang, Mingcheng; Qiu, Qian; Zeng, Shan; Shi, Maohua; Zou, Yaoyao; Ye, Yujin; Yang, Xia; Xu, Hanshi

doi:10.1093/rheumatology/kev312

Cited by 72 publications

(63 citation statements)

References 37 publications

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“…BET protein inhibitors have been shown to regulate general cytokine production through inhibition of recruitment of transcriptional machinery to gene promoter regions, and interruption of NF-κB target gene transcription [122–124]. Overall, pan-BET inhibitors are very effective at blocking NF-κB-driven secretion of pro-inflammatory cytokines through various mechanisms (Table 1).…”

Section: Bet Protein Regulation Of Inflammationmentioning

confidence: 99%

“…Overall, pan-BET inhibitors are very effective at blocking NF-κB-driven secretion of pro-inflammatory cytokines through various mechanisms (Table 1). In general, BET protein inhibition blocks the expression of the NF-κB target genes (Table 1) induced by mediators, such as TNF-α and bacterial lipopolysaccharide (LPS) [122]. Not only does JQ1 block NF-κB target gene transcription, but JQ1 also prevents phosphorylation of IκB, the upstream negative regulator of NF-κB [122].…”

Section: Bet Protein Regulation Of Inflammationmentioning

confidence: 99%

“…In general, BET protein inhibition blocks the expression of the NF-κB target genes (Table 1) induced by mediators, such as TNF-α and bacterial lipopolysaccharide (LPS) [122]. Not only does JQ1 block NF-κB target gene transcription, but JQ1 also prevents phosphorylation of IκB, the upstream negative regulator of NF-κB [122]. In human macrophages, LPS activation of toll-like receptor 4 (TLR4) results in increased association of BRD4 with gene promoter regions [125, 126], whereas treatment with I-BET ablates this association [125].…”

Section: Bet Protein Regulation Of Inflammationmentioning

confidence: 99%

“…There are multiple demonstrations that BET protein inhibition decreases cytokine production (Table 1), including IL-6 (pleiotrophic), IL-17, and IL-1β, which are cytokines implicated in both diabetogenic inflammation and breast cancer [122, 132–134]. In 2010, the demonstration that the small molecule inhibitor JQ1 associates with the hydrophobic pocket of bromodomains to interrupt histone binding [110], and that I-BET762, a synthetic acetylated histone mimic, disrupts BET protein interaction with chromatin, suggested that JQ1 and I-BET762 might be useful tools to investigate the relationship between BET proteins and cytokine gene transcription [110, 132].…”

Section: Bet Protein Regulation Of Inflammationmentioning

confidence: 99%

“…Complementing in vitro studies, preclinical and animal models indicate that BET inhibitors are effective for the treatment of inflammatory diseases in vivo (Table 1). Administration of JQ1 alleviates inflammation in mouse models of psoriasis, rheumatoid, and osteoarthritis (RA and OA), and multiple sclerosis (MS) [122, 127, 133, 135]. The ability of BET inhibition to treat these inflammatory diseases effectively in mice implies that BET inhibitors may be useful for the treatment of chronic inflammation associated with obesity, T2D, and breast cancers through epigenetic disruption of cytokine networks.…”

Section: Bet Inhibitors and Clinical Applications For Inflammationmentioning

confidence: 99%

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BET bromodomain proteins and epigenetic regulation of inflammation: implications for type 2 diabetes and breast cancer

Nicholas

Andrieu

Strissel

et al. 2016

Cell. Mol. Life Sci.

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Chronic inflammation drives pathologies associated with type 2 diabetes (T2D) and breast cancer. Obesity-driven inflammation may explain increased risk and mortality of breast cancer with T2D reported in the epidemiology literature. Therapeutic approaches to target inflammation in both T2D and cancer have so far fallen short of the expected improvements in disease pathogenesis or outcomes. The targeting of epigenetic regulators of cytokine transcription and cytokine signaling offers one promising, untapped approach to treating diseases driven by inflammation. Recent work has deeply implicated the Bromodomain and Extra-Terminal domain (BET) proteins, which are acetylated histone “readers”, in epigenetic regulation of inflammation. This review focuses on inflammation associated with T2D and breast cancer, and the possibility of targeting BET proteins as an approach to regulating inflammation in the clinic. Understanding inflammation in the context of BET protein regulation may provide a basis for designing promising therapeutics for T2D and breast cancer.

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Section: Bet Protein Regulation Of Inflammationmentioning

confidence: 99%

Section: Bet Protein Regulation Of Inflammationmentioning

confidence: 99%

Section: Bet Protein Regulation Of Inflammationmentioning

confidence: 99%

Section: Bet Protein Regulation Of Inflammationmentioning

confidence: 99%

Section: Bet Inhibitors and Clinical Applications For Inflammationmentioning

confidence: 99%

See 3 more Smart Citations

BET bromodomain proteins and epigenetic regulation of inflammation: implications for type 2 diabetes and breast cancer

Nicholas

Andrieu

Strissel

et al. 2016

Cell. Mol. Life Sci.

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Reset of Inflammatory Priming of Joint Tissue and Reduction of the Severity of Arthritis Flares by Bromodomain Inhibition

Friščić

Reinwald

Böttcher

et al. 2023

Arthritis & Rheumatology

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OBJECTIVE: We have recently shown that priming of synovial fibroblasts (SFs) drives arthritis flares. Pathogenic priming of SFs is essentially mediated by epigenetic reprogramming. Bromodomain and extra-terminal motif (BET) proteins translate epigenetic changes into transcription. Here we used a BET inhibitor to target inflammatory tissue priming and reduce flare severity in experimental arthritis. METHODS: BALB/c mice were treated intraperitoneally or locally into the paw with I-BET151, which blocks interaction of BET proteins with acetylated histones. Effect of I-BET151 on acute arthritis and/or inflammatory tissue priming was assessed in a model of repeated injections of monosodium urate crystals or zymosan into the paw. I-BET151 was given either from before arthritis induction, at peak inflammation, or after healing of the first arthritis bout. Transcriptomic (RNA-Seq), epigenomic (ATAC-Seq) and functional analysis (invasion, cytokine production, migration, senescence, metabolic flux) was performed on murine and human SFs treated with I-BET151 in vitro or in vivo. RESULTS: Systemic I-BET151 administration did not affect acute inflammation but abolished inflammatory tissue priming and diminished flare severity in both preventive and therapeutic treatment settings. I-BET151 was also effective when applied locally in the joint. BET inhibition also inhibited osteoclast differentiation, while macrophage activation in the joint was not affected. Flare reduction after BET inhibition was mediated, at least in part, by rolling back the primed transcriptional, metabolic and pathogenic phenotype of SFs. CONCLUSION: Inflammatory tissue priming is dependent on transcriptional regulation by BET proteins, which makes them promising therapeutic targets for preventing arthritis flares in previously affected joints.

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Bromodomain‐containing protein 4 inhibition alleviates matrix degradation by enhancing autophagy and suppressing NLRP3 inflammasome activity in NP cells

Hong

Markova

et al. 2020

Journal Cellular Physiology

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An imbalance between matrix synthesis and degradation is the hallmark of intervertebral disc degeneration while inflammatory cytokines contribute to the imbalance. Bromodomain and extra‐terminal domain (BET) family is associated with the pathogenesis of inflammation, and inhibition of BRD4, a vital member of BET family, plays an anti‐inflammatory role in many diseases. However, it remains elusive whether BRD4 plays a similar role in nucleus pulposus (NP) cells and participates in the pathogenesis of intervertebral disc degeneration. The present study aims to observe whether BRD4 inhibition regulates matrix metabolism by controlling autophagy and NLRP3 inflammasome activity. Besides, the relationship was investigated among nuclear factor κB (NF‐κB) signaling, autophagy and NLRP3 inflammasome in NP cells. Here, real‐time polymerase chain reaction, western blot analysis and adenoviral GFP‐LC3 vector transduction in vitro were used, and it was revealed that BRD4 inhibition alleviated the matrix degradation and increased autophagy in the presence or absence of tumor necrosis factor α. Moreover, p65 knockdown or treatment with JQ1 and Bay11‐7082 demonstrated that BRD4 inhibition attenuated NLRP3 inflammasome activity through NF‐κB signaling, while autophagy inhibition by bafilomycin A1 promoted matrix degradation and NLRP3 inflammasome activity in NP cells. In addition, analysis of BRD4 messenger RNA expression in human NP tissues further verified the destructive function of BRD4. Simply, BRD4 inhibition alleviates matrix degradation by enhancing autophagy and suppressing NLRP3 inflammasome activity through NF‐κB signaling in NP cells.

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Bromodomain and extra-terminal domain bromodomain inhibition prevents synovial inflammation via blocking IκB kinase–dependent NF-κB activation in rheumatoid fibroblast-like synoviocytes

Abstract: This study implicates BET Brds as important regulators of IκB kinase/NF-κB-mediated synovial inflammation of RA and identifies BET proteins as novel therapeutic targets in inflammatory arthritis.

Cited by 72 publications

References 37 publications

BET bromodomain proteins and epigenetic regulation of inflammation: implications for type 2 diabetes and breast cancer

BET bromodomain proteins and epigenetic regulation of inflammation: implications for type 2 diabetes and breast cancer

Reset of Inflammatory Priming of Joint Tissue and Reduction of the Severity of Arthritis Flares by Bromodomain Inhibition

Bromodomain‐containing protein 4 inhibition alleviates matrix degradation by enhancing autophagy and suppressing NLRP3 inflammasome activity in NP cells

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