{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T10:38:32Z","timestamp":1775817512405,"version":"3.50.1"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T00:00:00Z","timestamp":1620950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Decreased human epididymis protein 4 (HE4) plasma levels were reported in cystic fibrosis (CF) patients under CFTR potentiator <jats:italic>ivacaftor<\/jats:italic> therapy, which inversely correlated with lung function improvement. In this study, we investigated whether HE4 expression was affected via modulation of CFTR function in CF bronchial epithelial (CFBE) cells <jats:italic>in vitro<\/jats:italic>. HE4 protein levels were measured in the supernatants of CFBE 41o<jats:sup>\u2212<\/jats:sup> cells expressing F508del-CFTR or wild-type CFTR (wt-CFTR) after administration of <jats:italic>lumacaftor\/ivacaftor<\/jats:italic> or <jats:italic>tezacaftor\/ivacaftor<\/jats:italic>, while HE4 expression in CFBE 41o<jats:sup>\u2212<\/jats:sup> cells were also analyzed following application of adenylate cyclase activators Forskolin\/IBMX or CFTR<jats:sub>inh172<\/jats:sub>. The effect of all of these compounds on CFTR function was monitored by the whole-cell patch-clamp technique. Induced HE4 expression was studied with interleukin-6 (IL-6) in F508del-CFTR CFBE 41o<jats:sup>\u2212<\/jats:sup> cells under TNF-\u03b1 stimulation for 1\u00a0h up to 1\u00a0week in duration. In parallel, plasma HE4 was determined in CF subjects homozygous for <jats:italic>p.Phe508del-CFTR<\/jats:italic> mutation receiving <jats:italic>lumacaftor\/ivacaftor<\/jats:italic> (Orkambi<jats:sup>\u00ae<\/jats:sup>) therapy. NF-\u03baB-mediated signaling was observed via the nuclear translocation of p65 subunit by fluorescence microscopy together with the analysis of IL-6 expression by an immunoassay. In addition, HE4 expression was examined after NF-\u03baB pathway inhibitor BAY 11-7082 treatment with or without CFTR modulators. CFTR modulators partially restored the activity of F508del-CFTR and reduced HE4 concentration was found in F508del-CFTR CFBE 41o<jats:sup>\u2212<\/jats:sup> cells that was close to what we observed in CFBE 41o<jats:sup>\u2212<\/jats:sup> cells with wt-CFTR. These data were in agreement with decreased plasma HE4 concentrations in CF patients treated with Orkambi<jats:sup>\u00ae<\/jats:sup>. Furthermore, CFTR inhibitor induced elevated HE4 levels, while CFTR activator Forskolin\/IBMX downregulated HE4 in the cell cultures and these effects were more pronounced in the presence of CFTR modulators. Higher activation level of baseline and TNF-\u03b1 stimulated NF-\u03baB pathway was detected in F508del-CFTR vs. wt-CFTR CFBE 41o<jats:sup>\u2212<\/jats:sup> cells that was substantially reduced by CFTR modulators based on lower p65 nuclear positivity and IL-6 levels. Finally, HE4 expression was upregulated by TNF-\u03b1 with elevated IL-6, and both protein levels were suppressed by combined administration of NF-\u03baB pathway inhibitor and CFTR modulators in CFBE 41o<jats:sup>\u2212<\/jats:sup> cells. In conclusion, CFTR dysfunction contributes to abnormal HE4 expression via NF-\u03baB in CF.<\/jats:p>","DOI":"10.3389\/fphar.2021.592184","type":"journal-article","created":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T08:04:53Z","timestamp":1620979493000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Enhanced Expression of Human Epididymis Protein 4 (HE4) Reflecting Pro-Inflammatory Status Is Regulated by CFTR in Cystic Fibrosis Bronchial Epithelial Cells"],"prefix":"10.3389","volume":"12","author":[{"given":"Zsolt","family":"Bene","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zsolt","family":"Fejes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tibor Gabor","family":"Szanto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ferenc","family":"Fenyvesi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judit","family":"V\u00e1radi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luka A.","family":"Clarke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gyorgy","family":"Panyi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr.","given":"Milan","family":"Macek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margarida D.","family":"Amaral","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Istv\u00e1n","family":"Balogh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr.","given":"B\u00e9la","family":"Nagy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1016\/j.jcf.2018.03.010","article-title":"CFTR Rescue with VX-809 and VX-770 Favors the Repair of Primary Airway Epithelial Cell Cultures from Patients with Class II Mutations in the Presence of Pseudomonas aeruginosa Exoproducts","volume":"17","author":"Adam","year":"2018","journal-title":"J. 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