Suppression of inflammation by a synthetic histone mimic
Edwige Nicodeme1, Kate L Jeffrey, Uwe Schaefer
1Centre de Recherche GSK, 27 Avenue du Québec, 91140 Villebon Sur Yvette, France.
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.
Insights
A new synthetic compound, I-BET, targets inflammatory gene expression by disrupting histone recognition in immune cells. This approach offers a novel strategy for developing immunomodulatory drugs to combat inflammatory diseases.
Area of Science:
- Immunology
- Pharmacology
- Molecular Biology
- Epigenetics
Background:
- Pathogen interaction with immune cells triggers inflammatory gene expression, crucial for defense but often harmful due to excessive protein production.
- Inflammatory response magnitude depends on upstream signaling proteins and chromatin complexes regulating mRNA expression.
- Recognition of post-translationally modified histones by nuclear proteins is critical for initiating mRNA transcription and elongation.
Purpose of the Study:
- To present a novel pharmacological strategy targeting inflammatory gene expression.
- To investigate the disruption of acetylated histone recognition by bromodomain and extra terminal domain (BET) proteins.
- To evaluate a synthetic compound (I-BET) for its potential as an immunomodulatory drug.
Main Methods:
- Development of a synthetic compound, I-BET, designed to mimic acetylated histones.
- Testing I-BET's ability to disrupt chromatin complexes involved in inflammatory gene expression in activated macrophages.
- Assessing I-BET's protective effects against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis in vivo.
Main Results:
- The synthetic compound I-BET effectively mimics acetylated histones, interfering with BET protein recognition.
- I-BET disrupts chromatin complexes, significantly reducing the expression of key inflammatory genes in activated macrophages.
- Administration of I-BET conferred protection against both endotoxic shock and bacterial sepsis in experimental models.
Conclusions:
- Targeting proteins that recognize post-translationally modified histones represents a novel therapeutic avenue.
- Synthetic compounds like I-BET can modulate inflammatory gene expression by interfering with epigenetic readers.
- This approach holds promise for developing a new generation of immunomodulatory drugs for inflammatory conditions.
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