{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T20:19:57Z","timestamp":1773778797214,"version":"3.50.1"},"reference-count":34,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T00:00:00Z","timestamp":1730160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["23K07658"],"award-info":[{"award-number":["23K07658"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Steroid-resistant asthma is a common cause of refractory asthma. Type 2 inflammation is the main inflammatory response in asthma, and the mechanism underlying the steroid-resistance of type 2 inflammation has not been completely elucidated. Tumor-necrosis-factor-like apoptosis-inducing factor (TWEAK) and transforming growth factor (TGF)-\u03b21 are involved in epithelial\u2013mesenchymal transition (EMT) and the production of thymic stromal lymphopoietin (TSLP) and C-C motif chemokine ligand 5 (CCL5). We herein hypothesize that the combined exposure to TWEAK and TGF-\u03b21 may result in the development of steroid resistance in bronchial epithelial cells. The bronchial epithelial cell line BEAS-2B was cultured with or without TGF-\u03b21 or TWEAK, in the presence or absence of dexamethasone (DEX). The roles of Smad-independent pathways and MAP kinase phosphatase 1 (MKP-1) were also explored. Co-stimulation of TWEAK and TGF-\u03b21 induced E-cadherin reduction, N-cadherin upregulation, and TSLP and CCL5 production, which were not suppressed by DEX. Inhibition of the nuclear factor kappa beta (NF-\u03baB) and mitogen-activated protein kinase pathways downregulated steroid-unresponsive TSLP and CCL5 production, whereas knockdown of MKP-1 improved steroid-unresponsive TSLP production, induced by co-stimulation with TWEAK and TGF-\u03b21. Therefore, co-stimulation with TWEAK and TGF-\u03b21 can induce the steroid-insensitive production of TSLP and CCL5 in the bronchial epithelium and may contribute to airway inflammation.<\/jats:p>","DOI":"10.3390\/ijms252111625","type":"journal-article","created":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T10:45:35Z","timestamp":1730198735000},"page":"11625","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Co-Stimulation with TWEAK and TGF-\u03b21 Induces Steroid-Insensitive TSLP and CCL5 Production in BEAS-2B Human Bronchial Epithelial Cells"],"prefix":"10.3390","volume":"25","author":[{"given":"Sumiko","family":"Abe","sequence":"first","affiliation":[{"name":"Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0962-5731","authenticated-orcid":false,"given":"Norihiro","family":"Harada","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo 113-8421, Japan"},{"name":"Research Institute for Diseases of Old Ages, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo 113-8421, Japan"},{"name":"Atopy (Allergy) Research Center, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1388-3693","authenticated-orcid":false,"given":"Yuuki","family":"Sandhu","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hitoshi","family":"Sasano","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1463-2749","authenticated-orcid":false,"given":"Yuki","family":"Tanabe","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3263-1312","authenticated-orcid":false,"given":"Shoko","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takayasu","family":"Nishimaki","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1848-1512","authenticated-orcid":false,"given":"Yoshihiko","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomohito","family":"Takeshige","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonoko","family":"Harada","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo 113-8421, Japan"},{"name":"Atopy (Allergy) Research Center, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hisaya","family":"Akiba","sequence":"additional","affiliation":[{"name":"Department of Immunology, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5749-4118","authenticated-orcid":false,"given":"Kazuhisa","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo 113-8421, Japan"},{"name":"Research Institute for Diseases of Old Ages, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo 113-8421, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3649","DOI":"10.1096\/fj.09-134684","article-title":"Glucocorticoid-induced leucine zipper (GILZ): A new important mediator of glucocorticoid action","volume":"23","author":"Ayroldi","year":"2009","journal-title":"FASEB J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/j.1476-5381.2010.01199.x","article-title":"Glucocorticosteroids: Current and future directions","volume":"163","author":"Barnes","year":"2011","journal-title":"Br. 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