Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/32575
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dc.contributor.authorGavrila, Adelina-
dc.contributor.authorChachi, Latifa-
dc.contributor.authorTliba, Omar-
dc.contributor.authorBrightling, Christopher-
dc.contributor.authorAmrani, Yassine-
dc.date.accessioned2015-07-10T10:39:30Z-
dc.date.available2015-07-10T10:39:30Z-
dc.date.issued2015-04-21-
dc.identifier.citationAmerican Journal of Respiratory Cell and Molecular Biology, 2015, DOI: 10.1165/rcmb.2014-0477OCen
dc.identifier.issn1044-1549-
dc.identifier.urihttp://www.atsjournals.org/doi/10.1165/rcmb.2014-0477OC#.VZ-ZBUbK-5Ien
dc.identifier.urihttp://hdl.handle.net/2381/32575-
dc.description.abstractPreclinical models of human conditions including asthma showed the therapeutic potential of compound A (CpdA), a dissociated glucocorticoid (GC) receptor (GRα) ligand. Whether CpdA inhibits GC resistance, a central feature of severe asthma, has not been addressed. We investigated whether CpdA modulates cytokine-induced GC resistance in human airway smooth muscle (ASM) cells. Healthy and asthmatic ASM cells were treated with TNFα/IFNγ for 24 hr in the presence or absence of CpdA. ELISA and qPCR assays were used to assess the effect of CpdA on chemokine expression. Activation of GRα by CpdA was assessed by qPCR, immunostaining and receptor antagonism using RU486. An effect of CpdA on the transcription factor IRF-1 was investigated using immunoblot, immunostaining and siRNA knockdown. CpdA inhibited production of fluticasone-resistant chemokines CCL5, CX3CL1, and CXCL10 at protein and mRNA levels in both asthmatic and healthy cells. CpdA failed to induce expression of Glucocorticoid-induced Leucine Zipper (GILZ) while transiently inducing MAPK phosphatase 1 (MKP-1) at both mRNA and protein levels. CpdA inhibitory action was not associated with GRαnuclear translocation nor prevented by RU486 antagonism. Activation of IRF-1 by TNFα/IFNγ was inhibited by CpdA. IRF-1 siRNA knockdown reduced cytokine-induced CCL5 and CX3CL1 production. siRNA MKP-1 prevented the inhibitory effect of CpdA on cytokine-induced CXCL10 production. For the first time, we show that CpdA inhibits the production of GC-resistant chemokines via GRα-independent mechanisms involving the inhibition of IRF-1 and up-regulation of MKP-1. Thus, targeting CpdA sensitive pathways in ASM cells represents an alternative therapeutic approach to treat GC resistance in asthma.en
dc.language.isoenen
dc.publisherAmerican Thoracic Societyen
dc.relation.urihttp://www.ncbi.nlm.nih.gov/pubmed/25897650-
dc.rightsCopyright © 2015, American Thoracic Society. Deposited with reference to the publisher’s archiving policy available on the SHERPA/RoMEO website.en
dc.subjectTranscription factorsen
dc.subjectasthma therapiesen
dc.subjectchemokinesen
dc.subjectrefractory patientsen
dc.subjectsevere asthmaen
dc.titleThe Plant Derivative Compound A Inhibits the Production of Corticosteroid-resistant Chemokines by Airway Smooth Muscle Cells.en
dc.typeJournal Articleen
dc.identifier.doi10.1165/rcmb.2014-0477OC-
dc.identifier.eissn1535-4989-
dc.description.statusPeer-revieweden
dc.description.versionPost-printen
dc.type.subtypeJOURNAL ARTICLE-
pubs.organisational-group/Organisationen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGYen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicineen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Infection, Immunity and Inflammationen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/Themesen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/Themes/Molecular & Cellular Bioscienceen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/Themes/Respiratory Scienceen
dc.dateaccepted2015-04-20-
Appears in Collections:Published Articles, Dept. of Infection, Immunity and Inflammation

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