Cystic Fibrosis (CF) lung disease is characterised by a chronic and exaggerated inﬂammation in the airways. Despite recent developments to therapeutically overcome the underlying functional defect in CFTR (cystic ﬁbrosis transmembrane conductance regulator), there is still an unmet need to also normalise the inﬂammatory response. The prolonged and heightened inﬂammatory response in CF is in part mediated by a lack of intrinsic downregulation of the pro-inﬂammatory NF-kB pathway. We have previously identiﬁed reduced expression of the NF-kB down-regulator A20 in CF as a key target to normalise the inﬂammatory response. Here we have used publically available gene array expression data together with sscMap (statistically signiﬁcant connections’map)to successfully predict drugs already licensed for the use in humans to induce A20 mRNA and protein expression and thereby reduce inﬂammation. The effect of the predicted drugs on A20 and NFkB (p65) expression (mRNA) as well as pro-inﬂammatory cytokine release (IL-8) in the presence and absence of bacterial LPS was shown in bronchial epithelial cells lines (16HBE14o-, CFBE41o-) and in primary nasal epithelial cells (PNECs) from patients with CF (Phe508del homozygous) and non-CF controls. Additionally, the speciﬁcity of the drug action on A20 was conﬁrmed using cell lines with TNFAIP3 (A20) knockdown (siRNA). We also show that the A20 inducing effect of ikarugamycin and quercetin is lower in CF derived airway epithelial cells than in non-CF cells.
|Number of pages||10|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Early online date||10 Jun 2016|
|Publication status||Published - 28 Jun 2016|
- A20 , NF-kB, Connectivity Mapping, Drug repositioning, CF airways inflammation
Malcomson, B., Wilson, H., Thillaiyampalan, G., Barsden, R., Donegan, S., El Banna, A., Elborn, J., Ennis, M., Kelly, C., Zhang, S-D., & Schock, B. (2016). Connectivity Mapping (ssCMap) To Predict A20 Inducing Drugs: Anti-inﬂammatory Action In Cystic Fibrosis. Proceedings of the National Academy of Sciences of the United States of America, 113(26), E3725–E3734. https://doi.org/10.1073/pnas.1520289113