How corticosteroids control inflammation: Quintiles Prize Lecture 2005

Area of Science:

• Molecular Biology
• Immunology
• Pharmacology

Background:

• Chronic inflammation involves gene activation by transcription factors like NF-κB and AP-1.
• Corticosteroids suppress inflammation by reversing histone acetylation via glucocorticoid receptors (GR) and histone deacetylase-2 (HDAC2).
• Corticosteroid resistance in COPD and severe asthma is linked to reduced HDAC2 activity caused by oxidative stress.

Purpose of the Study:

• To investigate the mechanism of corticosteroid resistance in chronic inflammatory diseases.
• To explore the role of HDAC2 in corticosteroid responsiveness.
• To identify potential therapeutic strategies to overcome corticosteroid resistance.

Main Methods:

• Analysis of gene expression and histone acetylation in inflammatory cells.
• Investigation of the interaction between GR, coactivators, and HDAC2.
• Assessment of the effects of theophylline on HDAC2 activity and inflammatory gene expression.

Main Results:

• Reduced HDAC2 activity and expression were observed in patients with COPD, severe asthma, and smokers.
• Oxidative/nitrative stress was identified as a key factor in diminishing HDAC2 function.
• Theophylline demonstrated the potential to activate HDAC2 and reverse corticosteroid resistance in preclinical models.

Conclusions:

• HDAC2 dysfunction is a critical mechanism underlying corticosteroid resistance in severe inflammatory lung diseases.
• Targeting HDAC2 activation, potentially with agents like theophylline, represents a promising therapeutic avenue.
• This research paves the way for novel anti-inflammatory treatments for corticosteroid-resistant conditions.