@article {Khan3515, author = {Younis Khan and Paul Kirkham and Ian Adcock}, title = {Bromodomain mimics reduce oxidative stress-induced inflammation in human epithelial cells}, volume = {42}, number = {Suppl 57}, elocation-id = {3515}, year = {2013}, publisher = {European Respiratory Society}, abstract = {Background: Chronic obstructive pulmonary disease (COPD) is caused by prolonged cigarette smoke exposure and is associated with increased inflammation and oxidative stress under the control of histone acetylation. The recent development of bromodomain inhibitors which prevent the effects of histone acetylation may interfere with inflammatory gene expression.Method: Human epithelial (BEAS-2B) cells were stimulated with IL-1β (1ng/ml) in the presence or absence of H2O2 (100{\textmu}M) and the effect of pre-treatment with bromodomain inhibitors (JQ-1 and PFI-1) was investigated. Pro-inflammatory mediators (CXCL8 and IL-6) were measured by ELISA and transcripts by RT-PCR. H3 and H4 acetylation and recruitment of p65 and Brd4 to native promoters was investigated using chromatin immunoprecipitation (ChIP). The impact of Brd2 and Brd4 siRNA knockdown on inflammatory mediators was also investigated.Result: H2O2 enhanced IL1β-induced IL-6 and CXCL8 expression in BEAS-2B cells whereas H2O2 alone did not have any affect. H3 was acetylated at IL-6 and IL-8 promoters and this was associated with recruitment of both p65 and Brd4 proteins. The inactive Brd4 mimic (-)-JQ1 had no effect on IL-6 or CXCL8 expression whereas the active enantiomer (+)-JQ1 and PFI-1 reduced IL-6 and CXCL8 expression significantly. Brd4, but not Brd2, knockdown markedly reduced IL-6 and CXCL8 release. JQ-1 also inhibited p65 and Brd4 recruitment to the IL-6 and IL-8 promoters.Conclusion: The oxidative stress (H2O2) enhanced IL1β-induced IL-6 and CXCL8 expression was significantly reduced by JQ-1 and PFI-1. Brd4 plays an important role in the induction of inflammation and provides a potential anti-inflammatory therapeutic target.}, issn = {0903-1936}, URL = {https://erj.ersjournals.com/content/42/Suppl_57/3515}, eprint = {https://erj.ersjournals.com/content/42/Suppl_57/3515.full.pdf}, journal = {European Respiratory Journal} }