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Although corticosteroids are effective in alleviating airway diseases, some children with more moderate-severe asthma phenotypes show CS resistance and exhibit significant airflow obstruction, persistent inflammation, and more frequent exacerbations. Previous studies have demonstrated that Th1 cytokines, such as TNF-\u03b1 and IFN-\u03b3, promote CS resistance in adult human airway smooth muscle (ASM). In the present study, using a human fetal ASM cell model, we tested the hypothesis that TNF-\u03b1\/IFN-\u03b3 induces CS resistance. In contrast to TNF-\u03b1 or IFN-\u03b3 alone, the combination of TNF-\u03b1\/IFN-\u03b3 blunted the ability of fluticasone propionate (FP) to reduce expression of the chemokines CCL5 and CXCL10 despite expression of key anti-inflammatory glucocorticoid receptor target genes being largely unaffected by TNF-\u03b1\/IFN-\u03b3. Expression of the NF-\u03baB subunit p65 and phosphorylation of Stat1 were elevated in cells treated with TNF-\u03b1\/IFN-\u03b3, an effect that remained in the presence of FP. siRNA knockdown studies demonstrated the effects of TNF-\u03b1\/IFN-\u03b3 on increased p65 are mediated by Stat1, a transcription factor activated by IFN-\u03b3. Expression of TNFAIP3, a negative regulator of NF-\u03baB activity, was not altered by TNF-\u03b1\/IFN-\u03b3. However, the effects of TNF-\u03b1\/IFN-\u03b3 were partially reduced by overexpression of TNFAIP3 but did not influence p65 expression. Together, these data suggest that IFN-\u03b3 augments the effects of TNF-\u03b1 on chemokines by enhancing expression of key inflammatory pathways in the presence of CS. Interactions between TNF-\u03b1- and IFN-\u03b3-mediated pathways may promote inflammation in asthmatic children resistant to CSs.<\/jats:p>","DOI":"10.1152\/ajplung.00547.2017","type":"journal-article","created":{"date-parts":[[2018,10,18]],"date-time":"2018-10-18T12:34:55Z","timestamp":1539866095000},"page":"L71-L81","source":"Crossref","is-referenced-by-count":70,"title":["Th1 cytokines TNF-\u03b1 and IFN-\u03b3 promote corticosteroid resistance in developing human airway smooth muscle"],"prefix":"10.1152","volume":"316","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0027-9545","authenticated-orcid":false,"suffix":"Jr.","given":"Rodney D.","family":"Britt","sequence":"first","affiliation":[{"name":"Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota"},{"name":"Center for Perinatal Research, The Research Institute at Nationwide Children\u2019s Hospital, Columbus, Ohio"},{"name":"Department of Pediatrics, The Ohio State University, Columbus, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Sasse","sequence":"additional","affiliation":[{"name":"Department of Medicine, National Jewish Health, Denver, Colorado"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina M.","family":"Pabelick","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota"},{"name":"Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony N.","family":"Gerber","sequence":"additional","affiliation":[{"name":"Department of Medicine, National Jewish Health, Denver, Colorado"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2968-224X","authenticated-orcid":false,"given":"Y. 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