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IL-6 trans-signaling in cystic fibrosis bronchial cells potentiates TNF-α-driven ICAM-1 expression

John Lin1, Lyvia Fourcade1, Lucie Roussel1

  • 1The Meakins-Christie Laboratories at the Research Institute of the McGill University Health Centre and Department of Medicine, McGill University, Montreal, QC, Canada.

Frontiers in Cell and Developmental Biology
|October 9, 2025
PubMed
Abstract

Insights

Interleukin-6 (IL-6) trans-signaling exacerbates lung inflammation in cystic fibrosis (CF) patients during pulmonary exacerbations (PEx). Targeting IL-6 trans-signaling may reduce neutrophil adhesion and lung damage in CF airways.

Area of Science:

  • Pulmonary Medicine
  • Immunology
  • Microbiology

Background:

  • Pseudomonas aeruginosa infections cause chronic airway inflammation in cystic fibrosis (CF).
  • Interleukin-6 (IL-6) plays a dual role in inflammation, with trans-signaling exacerbating inflammatory responses.
  • IL-6 is upregulated in CF airways during pulmonary exacerbations (PEx).

Purpose of the Study:

  • To investigate the role of IL-6 trans-signaling in neutrophilic inflammation and lung tissue damage during PEx in people with CF (pwCF).

Main Methods:

  • Measured soluble IL-6 receptor alpha (sIL-6Rα) levels in plasma from pwCF during PEx using ELISA.
  • Investigated IL-6 signaling pathways via STAT3 phosphorylation in CF and non-CF cell lines.
  • Assessed ICAM-1 expression using flow cytometry.

Main Results:

  • pwCF exhibited elevated sIL-6Rα levels during PEx, indicating increased IL-6 trans-signaling.
  • CF bronchial cell lines showed heightened responsiveness to IL-6 trans-signaling compared to non-CF cells.
  • ICAM-1, a promoter of neutrophil adhesion, was upregulated by combined TNF-α and IL-6 signaling in CF cells.

Conclusions:

  • IL-6 trans-signaling contributes to neutrophilic inflammation and lung damage in CF during PEx.
  • Soluble IL-6Rα protects IL-6 from bacterial degradation, sustaining inflammation.
  • Targeting IL-6 trans-signaling presents a potential therapeutic strategy to mitigate lung damage in CF PEx.
Keywords:
ICAM-1IL-6 trans-signalingPseudomonas aeruginosacystic fibrosiscystic fibrosis transmembrane regulatorinflammationpulmonary exacerbations

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