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It is unclear whether IL-6 is a marker of critical illness or a mechanistic biomarker of pulmonary vascular remodelling. We hypothesised that IL-6 is produced by pulmonary vascular cells and sought to explore IL-6 associations with phenotypes and outcomes across diverse subtypes in a large PAH cohort.<\/jats:p><jats:p>IL-6 protein and gene expression levels were measured in cultured pulmonary artery smooth muscle cells (PASMCs) and endothelial cells (PAECs) from PAH patients and healthy controls. Serum IL-6 was measured in 2017 well-characterised PAH subjects representing each PAH subgroup. Relationships between IL-6 levels, clinical variables, and mortality were analysed using regression models.<\/jats:p><jats:p>Significantly higher IL-6 protein and gene expression levels were produced by PASMCs than by PAECs in PAH (p&lt;0.001), while there was no difference in IL-6 between cell types in controls. Serum IL-6 was highest in PAH related to portal hypertension and connective tissue diseases (CTD-PAH). In multivariable modelling, serum IL-6 was associated with survival in the overall cohort (hazard ratio 1.22, 95% CI 1.08\u20131.38; p&lt;0.01) and in IPAH, but not in CTD-PAH. IL-6 remained associated with survival in low-risk subgroups of subjects with mild disease.<\/jats:p><jats:p>IL-6 is released from PASMCs, and circulating IL-6 is associated with specific clinical phenotypes and outcomes in various PAH subgroups, including subjects with less severe disease. IL-6 is a mechanistic biomarker, and thus a potential therapeutic target, in certain PAH subgroups.<\/jats:p>","DOI":"10.1183\/13993003.01761-2019","type":"journal-article","created":{"date-parts":[[2020,2,6]],"date-time":"2020-02-06T20:25:17Z","timestamp":1581020717000},"page":"1901761","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":77,"title":["Cellular sources of interleukin-6 and associations with clinical phenotypes and outcomes in pulmonary arterial hypertension"],"prefix":"10.1183","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2388-5660","authenticated-orcid":false,"given":"Catherine E.","family":"Simpson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny Y.","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel 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