Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis.
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.
Centre for Experimental Medicine, Queen's University of Belfast, Belfast BT9 7AE, United Kingdom;
Beth
B
Malcomson
Centre for Experimental Medicine, Queen's University of Belfast, Belfast BT9 7AE, United Kingdom;
Hollie
H
Wilson
Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, 10125 Turin, Italy;
Eleonora
E
Veglia
Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast BT9 7AE, United Kingdom;
Gayathri
G
Thillaiyampalam
Centre for Experimental Medicine, Queen's University of Belfast, Belfast BT9 7AE, United Kingdom;
Ruth
R
Barsden
Centre for Experimental Medicine, Queen's University of Belfast, Belfast BT9 7AE, United Kingdom;
Shauna
S
Donegan
Centre for Experimental Medicine, Queen's University of Belfast, Belfast BT9 7AE, United Kingdom;
Amal
A
El Banna
Centre for Experimental Medicine, Queen's University of Belfast, Belfast BT9 7AE, United Kingdom;
Joseph S
JS
Elborn
Centre for Experimental Medicine, Queen's University of Belfast, Belfast BT9 7AE, United Kingdom;
Madeleine
M
Ennis
Northern Ireland Centre for Stratified Medicine, University of Ulster, Londonderry BT47 6SB, United Kingdom.
Catriona
C
Kelly
Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast BT9 7AE, United Kingdom; Northern Ireland Centre for Stratified Medicine, University of Ulster, Londonderry BT47 6SB, United Kingdom.
Shu-Dong
SD
Zhang
Centre for Experimental Medicine, Queen's University of Belfast, Belfast BT9 7AE, United Kingdom; b.schock@qub.ac.uk.
Bettina C
BC
Schock
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology; D007769:Lactams / Q000494:pharmacology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D011794:Quercetin / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology; D059467:Transcriptome; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000235:genetics* / Q000276:immunology
D000893:Anti-Inflammatory Agents; D016209:Interleukin-8; D007769:Lactams; D016328:NF-kappa B; C074292:ikarugamycin; D011794:Quercetin; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
A20; CF airway inflammation; NF-κB; connectivity mapping; drug repositioning