RT Journal Article SR Electronic T1 Cellular sources of interleukin-6 and associations with clinical phenotypes and outcomes in pulmonary arterial hypertension JF European Respiratory Journal JO Eur Respir J FD European Respiratory Society SP 1901761 DO 10.1183/13993003.01761-2019 VO 55 IS 4 A1 Catherine E. Simpson A1 Jenny Y. Chen A1 Rachel L. Damico A1 Paul M. Hassoun A1 Lisa J. Martin A1 Jun Yang A1 Melanie Nies A1 Megan Griffiths A1 Dhananjay Vaidya A1 Stephanie Brandal A1 Michael W. Pauciulo A1 Katie A. Lutz A1 Anna W. Coleman A1 Eric D. Austin A1 Dunbar D. Ivy A1 William C. Nichols A1 Allen D. Everett YR 2020 UL http://erj.ersjournals.com/content/55/4/1901761.abstract AB The pro-inflammatory cytokine interleukin (IL)-6 has been associated with outcomes in small pulmonary arterial hypertension (PAH) cohorts composed largely of patients with severe idiopathic PAH (IPAH). 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.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.Significantly higher IL-6 protein and gene expression levels were produced by PASMCs than by PAECs in PAH (p<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 1.08–1.38; p<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.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.Circulating IL-6, a pro-inflammatory cytokine produced by pulmonary arterial smooth muscle cells, is significantly associated with clinical phenotypes and survival in pulmonary arterial hypertension, which may guide individualised disease management https://bit.ly/3awkkSz