Abstract
Interaction of pathogens with cells of the immune system results in activation of inflammatory gene expression. This response, although vital for immune defence, is frequently deleterious to the host due to the exaggerated production of inflammatory proteins. The scope of inflammatory responses reflects the activation state of signalling proteins upstream of inflammatory genes as well as signal-induced assembly of nuclear chromatin complexes that support mRNA expression. Recognition of post-translationally modified histones by nuclear proteins that initiate mRNA transcription and support mRNA elongation is a critical step in the regulation of gene expression. Here we present a novel pharmacological approach that targets inflammatory gene expression by interfering with the recognition of acetylated histones by the bromodomain and extra terminal domain (BET) family of proteins. We describe a synthetic compound (I-BET) that by 'mimicking' acetylated histones disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, and confers protection against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis. Our findings suggest that synthetic compounds specifically targeting proteins that recognize post-translationally modified histones can serve as a new generation of immunomodulatory drugs.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation / drug effects
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Animals
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / pharmacology*
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Anti-Inflammatory Agents / therapeutic use
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Benzodiazepines
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Cells, Cultured
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Epigenomics
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Gene Expression Regulation / drug effects*
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Genome-Wide Association Study
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Heterocyclic Compounds, 4 or More Rings / chemistry
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Heterocyclic Compounds, 4 or More Rings / pharmacology*
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Heterocyclic Compounds, 4 or More Rings / therapeutic use
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Histone Deacetylase Inhibitors / pharmacology
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Hydroxamic Acids / pharmacology
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Inflammation* / drug therapy
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Inflammation* / prevention & control
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Kaplan-Meier Estimate
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Lipopolysaccharides / pharmacology
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Macrophages / drug effects*
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Mice
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Mice, Inbred C57BL
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Models, Molecular
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Protein Serine-Threonine Kinases / metabolism
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Protein Structure, Tertiary
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Salmonella Infections / drug therapy
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Salmonella Infections / immunology
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Salmonella Infections / physiopathology
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Salmonella Infections / prevention & control
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Salmonella typhimurium
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Sepsis / drug therapy
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Sepsis / prevention & control
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Shock, Septic / drug therapy
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Shock, Septic / prevention & control
Substances
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Anti-Inflammatory Agents
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Heterocyclic Compounds, 4 or More Rings
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Lipopolysaccharides
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Benzodiazepines
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trichostatin A
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molibresib
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Protein Serine-Threonine Kinases
Associated data
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GEO/GSE21764
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GEO/GSE21910
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PDB/3P5O