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 normali...
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creator | Malcomson, Beth Wilson, Hollie Veglia, Eleonora Thillaiyampalam, Gayathri Barsden, Ruth Donegan, Shauna Banna, Amal El Elborn, Joseph S. Ennis, Madeleine Kelly, Catriona Zhang, Shu-Dong Schock, Bettina C. |
description | 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. |
doi_str_mv | 10.1073/pnas.1520289113 |
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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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1520289113</identifier><identifier>PMID: 27286825</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Anti-Inflammatory Agents - pharmacology ; Autoimmune diseases ; Biological Sciences ; Cystic Fibrosis - drug therapy ; Cystic Fibrosis - genetics ; Cystic Fibrosis - immunology ; Epithelial Cells - drug effects ; Epithelial Cells - immunology ; Gene expression ; Gene loci ; Genomics ; Humans ; Interleukin-8 - genetics ; Interleukin-8 - immunology ; Lactams - pharmacology ; NF-kappa B - genetics ; NF-kappa B - immunology ; PNAS Plus ; Polymorphism ; Quercetin - pharmacology ; Respiratory Mucosa - drug effects ; Respiratory Mucosa - immunology ; Rheumatoid arthritis ; Transcriptome ; Tumor Necrosis Factor alpha-Induced Protein 3 - genetics ; Tumor Necrosis Factor alpha-Induced Protein 3 - immunology</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2016-06, Vol.113 (26), p.E3725-E3734</ispartof><rights>Volumes 1–89 and 106–113, copyright as a collective work only; author(s) retains copyright to individual articles</rights><rights>Copyright National Academy of Sciences Jun 28, 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-6811de16fcf2c7537929fe192ff316a1a38988aa753d250c1cc87fb1d51bf1ec3</citedby><cites>FETCH-LOGICAL-c443t-6811de16fcf2c7537929fe192ff316a1a38988aa753d250c1cc87fb1d51bf1ec3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26470664$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26470664$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27286825$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Malcomson, Beth</creatorcontrib><creatorcontrib>Wilson, Hollie</creatorcontrib><creatorcontrib>Veglia, Eleonora</creatorcontrib><creatorcontrib>Thillaiyampalam, Gayathri</creatorcontrib><creatorcontrib>Barsden, Ruth</creatorcontrib><creatorcontrib>Donegan, Shauna</creatorcontrib><creatorcontrib>Banna, Amal El</creatorcontrib><creatorcontrib>Elborn, Joseph S.</creatorcontrib><creatorcontrib>Ennis, Madeleine</creatorcontrib><creatorcontrib>Kelly, Catriona</creatorcontrib><creatorcontrib>Zhang, Shu-Dong</creatorcontrib><creatorcontrib>Schock, Bettina C.</creatorcontrib><title>Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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). 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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.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>27286825</pmid><doi>10.1073/pnas.1520289113</doi><oa>free_for_read</oa></addata></record> |
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subjects | Anti-Inflammatory Agents - pharmacology Autoimmune diseases Biological Sciences Cystic Fibrosis - drug therapy Cystic Fibrosis - genetics Cystic Fibrosis - immunology Epithelial Cells - drug effects Epithelial Cells - immunology Gene expression Gene loci Genomics Humans Interleukin-8 - genetics Interleukin-8 - immunology Lactams - pharmacology NF-kappa B - genetics NF-kappa B - immunology PNAS Plus Polymorphism Quercetin - pharmacology Respiratory Mucosa - drug effects Respiratory Mucosa - immunology Rheumatoid arthritis Transcriptome Tumor Necrosis Factor alpha-Induced Protein 3 - genetics Tumor Necrosis Factor alpha-Induced Protein 3 - immunology |
title | Connectivity mapping (ssCMap) to predict A20-inducing drugs and their antiinflammatory action in cystic fibrosis |
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