Abstract
Rationale: Asthma is an inflammatory disease of the airways. The airway epithelium is a major source of inflammatory mediators and a key target for infection resulting in asthma exacerbations.
Histone modifications and their readers control inflammation in a stimulus-dependent manner. Selective drugs are available that target methyltransferases (MT) such as UNC0638, UNC0642, UNC1999, GSK 343 & PFI2, histone demethylases (KDM) including GSK-J1 & GSK-J4 and bromodomain containing proteins (BCP) such as JQ1+, bromosporine, GSK2801, SGCBP30.
Aims: To compare the effect of epigenetic tool compounds on inflammatory (IL-1b) and viral [poly(I:C)] activation of human bronchial epithelial cells.
Methods: BEAS2B cells were pre-treated with probes before activation by IL-1β (1ng/ml) or poly(I:C) (10μg/ml). Inflammation (CXCL8/IL-6) and Cell viability (MTT).
Results: The BCP inhibitors JQ1+ and bromosporine and the MT inhibitor UNC0638 attenuated poly(I:C)- and IL-1b-induced IL-6 release. UNC0642, and the KDM inhibitor GSK-J4 increased the release of poly(I:C)-induced IL-6 but limited effect on IL-1β-induced IL-6. Similar effects were seen on CXCL8 release. No drug had an effect on cell viability.
Conclusion: The results confirm the expected effects of BCP actions but highlights the complexity of the regulation of inflammatory genes and proliferation by histone methylation at H3K9 and H3K27. BCP-directed drugs may be effective in severe asthma.
- Copyright ©ERS 2015