PT  - JOURNAL ARTICLE
AU  - Peter Brook
AU  - Andrew Durham
AU  - Ian Adcock
TI  - Enhanced inflammatory gene expression in bronchial epithelial cells from asthmatic patients: Attenuation by a Brd4 mimic
DP  - 2014 Sep 01
TA  - European Respiratory Journal
PG  - 4862
VI  - 44
IP  - Suppl 58
4099  - http://erj.ersjournals.com/content/44/Suppl_58/4862.short
4100  - http://erj.ersjournals.com/content/44/Suppl_58/4862.full
SO  - Eur Respir J2014 Sep 01; 44
AB  - Rationale: Asthma is an inflammatory disease of the airways. The airway epithelium is a major source of inflammatory mediators. The transcription factor NF-kB drives inflammation by recruitment of transcriptional cofactors such as the bromodomain-containing protein Brd4. Brd4 binds acetylated lysine residues and links NF-kB activation with inflammatory gene expression and may represent a novel anti-inflammatory target.Aim: To determine whether human bronchial epithelium (HBE) cells from asthmatics have a greater inflammatory gene expression than from healthy subjects and if this is due to enhanced Brd4 and p65 interaction and binding inflammatory genes.Methods: Primary asthmatic and normal HBE cells were treated with JQ1 (200nM), a Brd4 inhibitor, or AS602868 (10µM), an NF-kB inhibitor. After IL-1β (1nM) stimulation the production of CXCL8, IL-6 and GM-CSF was measured. Co-immunoprecipitation was performed for p65 and Brd4 association. Chromatin Immunoprecipitation (ChIP) analysis of p65 and Brd4 binding to inflammatory gene promoters was performed in the presence of JQ1 and IL-1β.Results: Inflammatory gene expression was higher in asthmatic HBEs. NF-kB and Brd4 inhibition attenuated inflammatory gene and protein production in all HBEs. The association between Brd4 and p65 was similar in asthmatic and normal HBEs and unaffected by IL-1β stimulation. ChIP shows that JQ1 reduced p65 and Brd4 binding to IL8, IL6 and CSF2 promoters.Conclusion: Asthmatic HBE cells produce more inflammatory mediators than cells from healthy subjects that are not due to increased Brd4-NF-kB binding. Inhibiting Brd4 may prevent asthmatic inflammation.