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

Catherine Simpson, Jenny Y. Chen, Rachel L. Damico, Paul M. Hassoun, Lisa J. Martin, Jun Yang, Melanie Nies, Megan Griffiths, R. Dhananjay Vaidya, Stephanie Brandal, Michael W. Pauciulo, Katie A. Lutz, Anna W. Coleman, Eric D. Austin, Dunbar D. Ivy, William C. Nichols, Allen D. Everett

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalEuropean Respiratory Journal
Volume55
Issue number4
DOIs
StatePublished - Apr 1 2020

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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    Simpson, C., Chen, J. Y., Damico, R. L., Hassoun, P. M., Martin, L. J., Yang, J., Nies, M., Griffiths, M., Dhananjay Vaidya, R., Brandal, S., Pauciulo, M. W., Lutz, K. A., Coleman, A. W., Austin, E. D., Ivy, D. D., Nichols, W. C., & Everett, A. D. (2020). Cellular sources of IL-6 and associations with clinical phenotypes and outcomes in PAH. European Respiratory Journal, 55(4). https://doi.org/10.1183/13993003.01761-2019