gsk1210151a has been researched along with Inflammation* in 5 studies
5 other study(ies) available for gsk1210151a and Inflammation
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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 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 ( Topics: Animals; Azepines; Cytokines; Epithelial Cells; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Gingiva; Heterocyclic Compounds, 4 or More Rings; Humans; Inflammation; Mice; Periodontitis; Porphyromonas gingivalis; Triazoles | 2019 |
I-BET151 selectively regulates IL-6 production.
Orchestration of the inflammatory response is crucial for clearing pathogens. Although the production of multiple inflammatory cytokines has been thought to be regulated by common mechanisms, recent evidence indicates that the expression of some cytokines is differentially regulated by epigenetic regulatory mechanisms. In this study, we found that IL-6 production is selectively inhibited by the BET bromodomain protein (BRD) inhibitor I-BET151 in RAW264.7 cells stimulated with lipopolysaccharide (LPS), whereas I-BET151 did not alter the production of several other cytokines (TNFα, IL-1β and IL-10) at the concentration of IBET151 used. I-BET151 prevented the binding of CBP to the promoter of IL-6, but I-BET151 did not affect acetylation, phosphorylation, nuclear translocation, or DNA binding of p65-NF-κB. In vivo, I-BET151 treatment in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis decreased the early clinical symptoms, which are thought to be dependent on cytokine production. Altogether, these data suggest that targeting epigenetic-related proteins, such as BET proteins, may provide a strategy to reduce inflammation and the severity of inflammatory diseases, such as multiple sclerosis. Topics: Animals; Blotting, Western; Cells, Cultured; Chromatin Immunoprecipitation; Cytokines; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Heterocyclic Compounds, 4 or More Rings; Immunoprecipitation; Inflammation; Interleukin-6; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis; Myelin-Oligodendrocyte Glycoprotein; NF-kappa B; Peptide Fragments; Phosphorylation; Tuberculosis | 2014 |
Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation.
Emerging evidence suggests that RANKL-induced changes in chromatin state are important for osteoclastogenesis, but these epigenetic mechanisms are not well understood and have not been therapeutically targeted. In this study, we find that the small molecule I-BET151 that targets bromo and extra-terminal (BET) proteins that 'read' chromatin states by binding to acetylated histones strongly suppresses osteoclastogenesis. I-BET151 suppresses pathologic bone loss in TNF-induced inflammatory osteolysis, inflammatory arthritis and post-ovariectomy models. Transcriptome analysis identifies a MYC-NFAT axis important for osteoclastogenesis. Mechanistically, I-BET151 inhibits expression of the master osteoclast regulator NFATC1 by suppressing expression and recruitment of its newly identified upstream regulator MYC. MYC is elevated in rheumatoid arthritis macrophages and its induction by RANKL is important for osteoclastogenesis and TNF-induced bone resorption. These findings highlight the importance of an I-BET151-inhibited MYC-NFAT axis in osteoclastogenesis, and suggest targeting epigenetic chromatin regulators holds promise for treatment of inflammatory and oestrogen deficiency-mediated pathologic bone resorption. Topics: Animals; Bone Resorption; Cell Differentiation; Cells, Cultured; Epigenesis, Genetic; Female; Heterocyclic Compounds, 4 or More Rings; Humans; Inflammation; Mice; Mice, Inbred C57BL; NFATC Transcription Factors; Osteoclasts; Osteogenesis; Osteoporosis; Ovariectomy; RANK Ligand | 2014 |
Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells.
Epigenetic modifiers are an emerging class of anti-tumor drugs, potent in multiple cancer contexts. Their effect on spontaneously developing autoimmune diseases has been little explored. We report that a short treatment with I-BET151, a small-molecule inhibitor of a family of bromodomain-containing transcriptional regulators, irreversibly suppressed development of type-1 diabetes in NOD mice. The inhibitor could prevent or clear insulitis, but had minimal influence on the transcriptomes of infiltrating and circulating T cells. Rather, it induced pancreatic macrophages to adopt an anti-inflammatory phenotype, impacting the NF-κB pathway in particular. I-BET151 also elicited regeneration of islet β-cells, inducing proliferation and expression of genes encoding transcription factors key to β-cell differentiation/function. The effect on β cells did not require T cell infiltration of the islets. Thus, treatment with I-BET151 achieves a 'combination therapy' currently advocated by many diabetes investigators, operating by a novel mechanism that coincidentally dampens islet inflammation and enhances β-cell regeneration. Topics: Animals; CD4-Positive T-Lymphocytes; Diabetes Mellitus, Type 1; Epigenesis, Genetic; Female; Heterocyclic Compounds, 4 or More Rings; Inflammation; Insulin-Secreting Cells; Macrophages; Mice, Inbred NOD; Monocytes; NF-kappa B; Phenotype; Regeneration; Signal Transduction; Transcription, Genetic | 2014 |
Identification of a novel series of BET family bromodomain inhibitors: binding mode and profile of I-BET151 (GSK1210151A).
A novel series of quinoline isoxazole BET family bromodomain inhibitors are discussed. Crystallography is used to illustrate binding modes and rationalize their SAR. One member, I-BET151 (GSK1210151A), shows good oral bioavailability in both the rat and minipig as well as demonstrating efficient suppression of bacterial induced inflammation and sepsis in a murine in vivo endotoxaemia model. Topics: Animals; Binding Sites; Crystallography, X-Ray; Guinea Pigs; Heterocyclic Compounds, 4 or More Rings; Inflammation; Isoxazoles; Mice; Models, Molecular; Nerve Tissue Proteins; Protein Binding; Quinolines; Rats | 2012 |