Connectivity Mapping (ssCMap) To Predict A20 Inducing Drugs: Anti-inflammatory Action In Cystic Fibrosis

Beth Malcomson, Hollie Wilson, Gayathri Thillaiyampalan, Ruth Barsden, Shauna Donegan, Amal El Banna, Joseph Elborn, Madeleine Ennis, Catriona Kelly, Shu-Dong Zhang, Bettina Schock

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Abstract

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.
Original languageEnglish
Pages (from-to)E3725–E3734
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number26
Early online date10 Jun 2016
DOIs
Publication statusPublished - 28 Jun 2016

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Keywords

  • A20 , NF-kB, Connectivity Mapping, Drug repositioning, CF airways inflammation

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