Cellular sources of IL-6 and associations with clinical phenotypes and outcomes in PAH

The pro-inflammatory cytokine interleukin-6 (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 remodeling. We hypothesized 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-characterized PAH subjects representing each PAH subgroup. Relationships between IL-6 levels, clinical variables, and mortality were analyzed with 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 modeling, serum IL-6 was associated with survival in the overall cohort (HR 1.22, 95% CI 1.08-1.38, p<0.01) and in IPAH, though 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.