{"doi":"10.1016/j.ebiom.2025.105887","title":"The role of interleukin-6 signalling in pleural infection: observational and genetic analyses","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.","journal":"EBioMedicine","year":2025,"id":572604,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9571,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1479229,"name":"Alexander J. Robbins","orcid":"0000-0001-6929-5802","position":1,"is_corresponding":false},{"id":1361226,"name":"Rachel Scott","orcid":"0000-0001-5847-3378","position":2,"is_corresponding":false},{"id":1479573,"name":"Jodie Chalmers","orcid":null,"position":3,"is_corresponding":false},{"id":25373,"name":"Harrison I.W. Wright","orcid":"0009-0009-1900-163X","position":4,"is_corresponding":false},{"id":241472,"name":"Robin N. Beaumont","orcid":"0000-0003-0750-8248","position":5,"is_corresponding":false},{"id":1479230,"name":"Karen T Elvers","orcid":"0000-0001-5345-8662","position":6,"is_corresponding":false},{"id":22004,"name":"Michael N. Weedon","orcid":"0000-0002-6174-6135","position":7,"is_corresponding":false},{"id":362096,"name":"Nick Maskell","orcid":"0000-0002-1276-6500","position":8,"is_corresponding":false},{"id":342558,"name":"David Arnold","orcid":"0000-0003-3158-7740","position":9,"is_corresponding":false},{"id":805322,"name":"Fergus Hamilton","orcid":"0000-0002-9760-4059","position":10,"is_corresponding":false},{"id":1479572,"name":"Amerikos Argyriou","orcid":null,"position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T02:57:27.876396Z","pmid":"40819633","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}