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Glucocorticoids: effects on gene transcription
Ian M Adcock1, Kaz Ito, Peter J Barnes
1Department of Thoracic Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, UK. ian.adcock@ic.ac.uk
Proceedings of the American Thoracic Society
|August 23, 2005
Summary
Glucocorticoids reduce inflammation by interacting with transcription factors like nuclear factor-kappaB (NF-kappaB). This interaction influences gene expression and histone acetylation, impacting inflammatory and anti-inflammatory pathways.
Area of Science:
- Molecular Biology
- Immunology
- Pharmacology
Background:
- Glucocorticoids are potent anti-inflammatory agents.
- Their effects are mediated by the activated glucocorticoid receptor interacting with transcription factors.
- Key transcription factors include nuclear factor-kappaB (NF-kappaB) and activator protein-1.
Purpose of the Study:
- To elucidate the molecular mechanisms by which glucocorticoids exert anti-inflammatory effects.
- To understand why glucocorticoids selectively suppress inflammatory genes.
- To investigate the role of histone acetylation and deacetylation in glucocorticoid action and resistance.
Main Methods:
- Analysis of interactions between the activated glucocorticoid receptor and transcription factors (NF-kappaB, AP-1).
- Investigation of chromatin modifications, specifically histone acetylation and deacetylation.
- Exploration of the impact of oxidative stress (e.g., from cigarette smoke) on glucocorticoid response.
Main Results:
- Glucocorticoid receptor interactions with NF-kappaB modulate histone acetylation/deacetylation.
- NF-kappaB activation involves coactivator recruitment and histone acetylation for inflammatory gene expression.
- Glucocorticoids can also induce anti-inflammatory genes via similar mechanisms.
Conclusions:
- Glucocorticoid anti-inflammatory effects are linked to differential regulation of histone acetylation/deacetylation by the glucocorticoid receptor and NF-kappaB.
- Understanding these mechanisms is crucial for explaining selective gene suppression and glucocorticoid tolerance.
- Oxidative stress may contribute to glucocorticoid resistance in conditions like COPD via altered histone acetylation balance.