Cellular sources of interleukin-6 and associations with clinical phenotypes and outcomes in pulmonary arterial hypertension.

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.
Competing Interests: Conflict of interest: Catherine E. Simpson has nothing to disclose. Conflict of interest: Jenny Y. Chen has nothing to disclose. Conflict of interest: Rachel L. Damico has nothing to disclose. Conflict of interest: Paul M. Hassoun has nothing to disclose. Conflict of interest: Lisa J. Martin has nothing to disclose. Conflict of interest: Jun Yang has nothing to disclose. Conflict of interest: Melanie Nies has nothing to disclose. Conflict of interest: Megan Griffiths has nothing to disclose. Conflict of interest: R. Dhananjay Vaidya has nothing to disclose. Conflict of interest: Stephanie Brandal has nothing to disclose. Conflict of interest: Michael W. Pauciulo has nothing to disclose. Conflict of interest: Katie A. Lutz has nothing to disclose. Conflict of interest: Anna W. Coleman has nothing to disclose. Conflict of interest: Eric D. Austin has nothing to disclose. Conflict of interest: Dunbar D. Ivy has nothing to disclose. Conflict of interest: William C. Nichols has nothing to disclose. Conflict of interest: Allen D. Everett has nothing to disclose.
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