{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T17:23:29Z","timestamp":1767374609410,"version":"3.44.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:00:00Z","timestamp":1758585600000},"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. Cell Dev. Biol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p><jats:italic>Pseudomonas aeruginosa<\/jats:italic> is gram-negative <jats:italic>bacillus<\/jats:italic> that causes chronic airway infections, leading to severe pulmonary inflammation in cystic fibrosis. This bacterial infection is frequently associated with a massive recruitment of neutrophils and an abnormal increase in production of inflammatory cytokines. Among these cytokines, interleukin (IL)-6 has both anti- and pro-inflammatory properties able to signal through classic and trans-signaling pathways, respectively. Furthermore, IL-6 is known to be upregulated in CFTR-deficient bronchial cell lines in the presence of <jats:italic>Pseudomonas aeruginosa<\/jats:italic>-derived filtrates and in Pulmonary Exacerbations (PEx). In this study, we aimed to determine whether IL-6 trans-signaling could contribute to neutrophilic inflammation leading to lung tissue damage during PEx of people with CF (pwCF).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>sIL-6Ra expression was measured by ELISA in plasma samples from pwCF at baseline and during exacerbations. IL-6 signalling was investigate in CF and non-CF cell lines using immunoblotting of STAT3 phosphorylation. ICAM-1 cell surface expression was determined using flow cytometry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We show that pwCF had higher sIL-6R\u03b1 levels in their plasma during PEx, suggestive of IL-6 trans-signaling. Furthermore, we show that a CF bronchial cell line is hyper-responsive to both classic and trans-signaling, with the higher levels of activation occurring during trans-signaling when compared to two non-CF cell lines.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our data unveiled that ICAM-1, which promotes neutrophil adhesion, is upregulated by the combination of TNF-\u03b1 and IL-6 signaling in CF bronchial cells. Interestingly, soluble IL-6R (sIL-6R\u03b1) protects IL-6 from degradation by bacterial proteases. Therefore, we suggest that strategies which target IL-6 trans-signaling may alleviate ICAM-1 mediated neutrophil adhesion and reduce subsequent lung damage in PEx.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcell.2025.1566482","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T05:31:22Z","timestamp":1758605482000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["IL-6 trans-signaling in cystic fibrosis bronchial cells potentiates TNF-\u03b1-driven ICAM-1 expression"],"prefix":"10.3389","volume":"13","author":[{"given":"John","family":"Lin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lyvia","family":"Fourcade","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucie","family":"Roussel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Marabella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie","family":"B\u00e9rub\u00e9","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dao","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Rousseau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1186\/s12890-015-0062-7","article-title":"Clinical outcomes associated with Staphylococcus aureus and Pseudomonas aeruginosa airway infections in adult cystic fibrosis patients","volume":"15","author":"Ahlgren","year":"2015","journal-title":"BMC Pulm. 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