The role of interleukin-6 signalling in pleural infection: observational and genetic analyses

Argyriou, Amerikos, Robbins, Alex, Scott, Rachel, Chalmers, Jodie, Wright, Harrison I.W., Beaumont, Robin N., Elvers, Karen T., Weedon, Michael N., Maskell, Nick A., Arnold, David T. and Hamilton, Fergus W. 2025. The role of interleukin-6 signalling in pleural infection: observational and genetic analyses. EBioMedicine 119 , 105887. 10.1016/j.ebiom.2025.105887

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Abstract

Background Pleural infection is associated with marked local and systemic inflammation leading to significant morbidity. It may be possible to therapeutically augment this response and interleukin-6 is a key signalling cascade in inflammatory pathologies. Methods We performed a prospective observational study recruiting patients with pleural effusions secondary to infection and measured interleukin-6 in matched pleural fluid and serum (n = 76). We subsequently performed a large-scale, two sample Mendelian Randomisation study (1601 cases and 830,709 controls), using genetic variation at IL6R to proxy the effect of interleukin-6 inhibition on pleural infection and overcome confounding inherent in observational analyses. Findings Pleural interleukin-6 levels in infection were 5000-fold higher than matched serum levels (median 72,752 pg/ml vs. 15 pg/ml). Pleural interleukin-6 predicted systemic inflammation (neutrophil count, C- reactive protein), correlated with clinical markers of disease severity (effusion size, pH, glucose), and was strongly associated with length of hospital stay. In Mendelian randomisation analyses, interleukin-6 inhibition was predicted to have a large protective effect on the incidence of infection (OR 0.23; 95% CI 0.14–0.39 per standard deviation decrease in C- reactive protein). The effect size was larger than that seen in COVID-19 and coronary artery disease, where interleukin-6 inhibition has been successful in trials. Interpretation Multiple lines of evidence suggest pleural interleukin-6 drives pathology in pleural infection. Targeting interleukin-6 may hold promise and should be considered in randomised trials. Funding This study has been funded by the National Institutes of Health and Care Research Bristol Biomedical Research Centre.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Biosciences Research Institutes & Centres > Medicines Discovery Institute (MDI)
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Start Date: 2025-08-01
Publisher:	Elsevier
ISSN:	2352-3964
Date of First Compliant Deposit:	26 August 2025
Date of Acceptance:	1 August 2025
Last Modified:	26 Aug 2025 14:30
URI:	https://orca.cardiff.ac.uk/id/eprint/180664

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