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We investigated whether CpdA modulates cytokine-induced GC resistance in human airway smooth muscle (ASM) cells. Healthy and asthmatic ASM cells were treated with TNF-\u03b1\/IFN-\u03b3 for 24 hours in the presence or absence of CpdA. ELISA and quantitative PCR assays were used to assess the effect of CpdA on chemokine expression. Activation of GR\u03b1 by CpdA was assessed by quantitative PCR, immunostaining, and receptor antagonism using RU486. An effect of CpdA on the transcription factor interferon regulatory factor 1 (IRF-1) was investigated using immunoblot, immunostaining, and small interfering RNA (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 GC-induced Leucine Zipper while transiently inducing mitogen-activated protein kinase phosphatase 1 (MKP-1) at both mRNA and protein levels. CpdA inhibitory action was not associated with GR\u03b1 nuclear translocation, nor was it prevented by RU486 antagonism. Activation of IRF-1 by TNF-\u03b1\/IFN-\u03b3 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 GR\u03b1-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.<\/jats:p>","DOI":"10.1165\/rcmb.2014-0477oc","type":"journal-article","created":{"date-parts":[[2015,4,21]],"date-time":"2015-04-21T11:28:50Z","timestamp":1429615730000},"page":"728-737","source":"Crossref","is-referenced-by-count":17,"title":["Effect of the Plant Derivative Compound A on the Production of Corticosteroid-Resistant Chemokines in Airway Smooth Muscle Cells"],"prefix":"10.1093","volume":"53","author":[{"given":"Adelina","family":"Gavrila","sequence":"first","affiliation":[{"name":"Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Latifa","family":"Chachi","sequence":"additional","affiliation":[{"name":"Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom; 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