Role of IL-6 trans-signalling in pulmonary exacerbations in cystic fibrosis
Bibliographic record
Abstract
Cystic fibrosis (CF) is an inherited multisystem disease due to loss-of-function mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). In the respiratory tract, this manifests as exceedingly viscous mucous coupled with impaired mucociliary clearance. This provides a favorable environment for opportunistic infection by pathogens such as Pseudomonas Aeruginosa and subsequently results in dysregulated airway inflammation that exceeds the pathogenic load. The natural progression of CF is interrupted by acute worsening of symptoms, called Pulmonary Exacerbations (PE). Airway inflammation in PEs is neutrophil dominant accompanied by large amounts of cytokines, which lead to increased lung tissue damage and irreversible loss of lung function. One of these cytokines, IL-6, is multifunctional, with both anti and proinflammatory functions, and comprises two signalling pathways: classic and trans-signalling. Classic signalling occurs through the membrane-bound IL-6 receptor (IL-6R) and is proposed to be anti-inflammatory, while trans-signalling occurs through the soluble IL-6R and is proposed to be pro-inflammatory. Previously, IL-6 has been shown to be upregulated in CFTR-deficient bronchial cell lines in the presence of P. Aeruginosa-derived filtrates, and in PEs, is also upregulated in the circulation. In this study, we therefore sought to characterize the role of IL-6 signalling in PEs and propose that IL-6 trans-signalling may contribute to neutrophilic inflammation and subsequent lung function decline. Using in-vitro models, we showed that CF cell lines were more responsive to IL-6 signalling compared to non-CF cell lines, and that IL-6 trans-signalling had a larger downstream effect compared to classic signalling. Further, we showed that ICAM-1, which regulates neutrophil adhesion, is upregulated by IL-6 signalling in conjunction with TNF-α signalling, and that the soluble IL-6R protects IL-6 from degradation in an antagonistic environment. Therefore, through this study, we suggest that strategies which target IL-6 trans-signalling may alleviate ICAM-1 mediated neutrophil adhesion and reduce subsequent lung damage in PEs.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".