Bromodomain and Extra-Terminal Protein Inhibition Attenuates Neutrophil-dominant Allergic Airway Disease

Manni, Michelle L.; Mandalapu, Sivanarayana; Salmerón, Andrés; Lora, José M.; Kolls, Jay K.; Alcorn, John F.

doi:10.1038/srep43139

Cited by 13 publications

(13 citation statements)

References 39 publications

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“…1A-C). These findings aligned with previous reports demonstrating attenuation of inflammatory gene expression following BET inhibition (6) and a requisite role for BET proteins in T H 17 cell differentiation and inflammation (7,16,17). Previous studies in ALL and AML leukemic cell lines have found that mRNA expression levels of BRD2, BRD3, and BRD4 did not correlate with MK-8628induced loss of cell viability (6).…”

Section: Mk-8628 Regulates Key Transcripts In Activated Human T Lymphsupporting

confidence: 91%

“…Interestingly, our studies also uncovered a striking decrease in mRNA expression levels of GM-SCF in T lymphocytes activated in the presence of MK-8628, further underscoring the concept of leveraging BET inhibitors in autoimmune settings where GM-CSF promotes T H 17-mediated inflammation in murine models of autoimmunity. Consistent with this hypothesis, several studies have demonstrated a requisite role for BET proteins in directing T H 17 cell differentiation as well as T H 17mediated pathology in murine models of autoimmunity (16,17,38,39). Furthermore, the BET inhibitor JQ1 was able to impair LPSinduced maturation of DCs by inhibiting GM-CSF-mediated STAT5 activation and limiting the capacity of DCs to induce allogeneic T cell proliferation and cytokine production (40).…”

Section: Discussionmentioning

confidence: 74%

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BET Bromodomain Inhibition Suppresses Human T Cell Function

et al. 2019

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Bromodomain and extraterminal domain (BET) proteins help direct the differentiation of helper T cell subsets, but their role in activated T cell function has not been described in detail. In this study, we investigate various consequences of epigenetic perturbation in human T lymphocytes using MK-8628, a potent and highly selective inhibitor of BET proteins. MK-8628 reduces the expression of canonical transcripts directing the proliferation, activation, and effector function of T lymphocytes. Treatment with MK-8628 abolishes the expression of key cyclins required for cell cycle progression and induces G1 cell cycle arrest in TCR-activated lymphocytes. This antiproliferative phenotype partially results from T lymphocyte apoptosis, which is exacerbated by MK-8628. In naive and memory T cell subsets, MK-8628 antagonizes T cell activation and suppresses polyfunctional cytokine production. Collectively, our results describe potent immunosuppressive effects of BET inhibition on human T cell biology. These results have important implications for immune modulatory targeting of BET proteins in the settings of T cell-driven autoimmune inflammation. ImmunoHorizons, 2019, 3: 294-305.

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Section: Mk-8628 Regulates Key Transcripts In Activated Human T Lymphsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 74%

BET Bromodomain Inhibition Suppresses Human T Cell Function

et al. 2019

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“…where its protein has been shown to modulate transcription, in particular, in cell cycle-induced transcriptional activation. It has been reported recently that BRD2 protein inhibition attenuates neutrophil-dominant allergic airway disease in mice models [44]. On chromosome 8: one non-synonymous polymorphic variant was identi ed, rs16889462 that was reported previously encoding one of the zinc e ux transporters, solute carrier family 30 member 8 (SLC30A8)…”

Section: Resultsmentioning

confidence: 99%

Next Generation Exome Sequencing of paediatric Asthma Identifies Rare and Novel Variants in Candidate Genes

Bogari

Amin

Rayes

et al. 2020

Preprint

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Background: Multiple genes have been implicated to have a role in asthma predisposition by association studies. Paediatric patients often manifest more extensive disease and a particularly severe disease course. It is likely that genetic predisposition could play a more substantial role in this group. This study aims to identify the spectrum of rare and novel variation in known paediatric asthma susceptibility genes using whole exome sequencing-analysis in nine individual cases of childhood onset allergic asthma. Data were processed through an analytical pipeline to align sequence reads, conduct quality checks, identify and annotate variants where patient sequence differed from the reference sequence. Results: DNA samples from the nine children with a history of bronchial asthma diagnosis underwent targeted exome capture and sequencing. For each patient, the entire complement of rare variation within strongly associated candidate genes was catalogued. The analysis showed 21 variants in the subjects, 13 had been previously identified and 8 were novel. Also, amongst of which, nineteen were non-synonymous and 2 were nonsense. With regard to the novel variants, the 2 non-synonymous variants in the PRKG1 gene (PRKG1: p.C519W and PRKG1: p.G520W) were presented in 4 cases, and a non-synonymous variant in the MAVS gene (MAVS: p.A45V) was identified in 3 cases. The variants we found in this study will enrich the variants spectrum and build up the database in the Saudi population. Novel eight variants were identified in the study which provides more evidence in the genetic susceptibility in asthma among Saudi children.Conclusion: Screening a cohort of Saudi children for molecular identification of polymorphisms associated with allergic asthmatic response. These, together with the clinical phenotypes, revealed genetic determinants for paediatric asthma and also we compared to the similar previous reports. Providing a genetic screening map for the molecular genetic determinants of allergic disease in Saudi children, with the goal of reducing the impact of chronic diseases on the health and the economy. We belief that the advanced specified statistical filtration/annotation programs used in this study succeeded to release such results in preliminary study, exploring the genetic map of that disease in Saudi children.

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“…Other proinflammatory cytokines and chemokines produced by immune cells, such as the Th17 cytokines (e.g., IL‐17A/F, IL‐21, IL‐22) are also deregulated in T2D and are important for tumor cell migration, invasion, survival, and proliferation . The genes that encode many of these cytokines and chemokines are also positively regulated by one or more BET proteins . These reports suggest that new, small molecule BETi can also improve the inflammatory microenvironment for therapeutic benefit, especially in patients with T2D and other chronic inflammatory diseases that are comorbid with their cancers.…”

Section: Bet Proteins In Metabolic Inflammation and Breast Cancer In mentioning

confidence: 99%

BET proteins in abnormal metabolism, inflammation, and the breast cancer microenvironment

Andrieu

Shafran

Deeney

et al. 2018

Journal of Leukocyte Biology

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Obesity and its associated pathology Type 2 diabetes are two chronic metabolic and inflammatory diseases that promote breast cancer progression, metastasis, and poor outcomes. Emerging critical opinion considers unresolved inflammation and abnormal metabolism separately from obesity; settings where they do not co-occur can inform disease mechanism. In breast cancer, the tumor microenvironment is often infiltrated with T effector and T regulatory cells programmed by metabolic signaling. The pathways by which tumor cells evade immune surveillance, immune therapies, and take advantage of antitumor immunity are poorly understood, but likely depend on metabolic inflammation in the microenvironment. Immune functions are abnormal in metabolic disease, and lessons learned from preclinical studies in lean and metabolically normal environments may not translate to patients with obesity and metabolic disease. This problem is made more urgent by the rising incidence of breast cancer among women who are not obese but who have metabolic disease and associated inflammation, a phenotype common in Asia. The somatic BET proteins, comprising BRD2, BRD3, and BRD4, are new critical regulators of metabolism, coactivate transcription of genes that encode proinflammatory cytokines in immune cell subsets infiltrating the microenvironment, and could be important targets in breast cancer immunotherapy. These transcriptional coregulators are well known to regulate tumor cell progression, but only recently identified as critical for metabolism, metastasis, and expression of immune checkpoint molecules. We consider interrelationships among metabolism, inflammation, and breast cancer aggressiveness relevant to the emerging threat of breast cancer among women with metabolic disease, but without obesity.

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Bromodomain and Extra-Terminal Protein Inhibition Attenuates Neutrophil-dominant Allergic Airway Disease

Cited by 13 publications

References 39 publications

BET Bromodomain Inhibition Suppresses Human T Cell Function

BET Bromodomain Inhibition Suppresses Human T Cell Function

Next Generation Exome Sequencing of paediatric Asthma Identifies Rare and Novel Variants in Candidate Genes

BET proteins in abnormal metabolism, inflammation, and the breast cancer microenvironment

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