Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis

Beth Malcomson, Hollie Wilson, Eleonora Veglia, Gayathri Thillaiyampalam, Ruth Barsden, Shauna Donegan, Amal El Banna, Joseph S. Elborn, Madeleine Ennis, Catriona Kelly, Shu-Dong Zhang, Bettina C. Schock

Research output: Contribution to journalArticle

24 Citations (Scopus)
23 Downloads (Pure)

Abstract

Cystic fibrosis (CF) lung disease is characterized by chronic and exaggerated inflammation in the airways. Despite recent developments to therapeutically overcome the underlying functional defect in the cystic fibrosis transmembrane conductance regulator, there is still an unmet need to also normalize the inflammatory response. The prolonged and heightened inflammatory response in CF is, in part, mediated by a lack of intrinsic down-regulation of the proinflammatory NF-κB pathway. We have previously identified reduced expression of the NF-κB down-regulator A20 in CF as a key target to normalize the inflammatory response. Here, we have used publicly available gene array expression data together with a statistically significant connections’ map (sscMap) 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 NF-κB(p65) expression (mRNA) as well as proinflammatory 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 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 tnfαip3 (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 pages12
JournalProceedings of the National Academy of Sciences
Volume113
Issue number26
Early online date10 Jun 2016
DOIs
Publication statusPublished - 28 Jun 2016

Keywords

  • A20
  • NF-κB
  • connectivity mapping
  • drug repositioning
  • CF airway inflammation

Fingerprint Dive into the research topics of 'Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis'. Together they form a unique fingerprint.

Cite this