IL-6 receptor overexpression in pulmonary arterial smooth muscle cells in idiopathic pulmonary hypertension

Abstract

Background: Interleukin (IL)-6 has been linked to the prognosis of pulmonary arterial hypertension (PAH). However, precise contributions of IL-6 and its signaling system to PAH progression is unknown. Objectives: To study pathogenic roles of IL-6 cis- and trans-signaling in experimental and human PAH and to evaluate the translational potential of IL-6 signaling inhibition. Methods: We examined the global expression pattern of key actors of the IL-6 signaling in human lung tissues, blood samples and cultured pulmonary artery smooth muscle cells (PASMCs) of 10 controls and 10 idiopathic PAH (IPAH) patients. In addition, two complementary animal PAH models have been explored: the Sugen 5416 plus chronic hypoxia and the monocrotaline rat models. Results: In IPAH, serum levels of IL-6 and soluble IL-6 receptors (sIL-6R) proteins were higher than in control subjects. We also found stronger immunoreactivity for IL-6R, phospho-STAT3 and Mcl-1 (myeloid leukemia-cell protein 1) in PASMCs of remodeled pulmonary arteries and cultured PASMCs of IPAH patients compared with controls. These abnormalities in the IL-6/IL-6R signaling were also histologically found in the two rat models. Consistent with these findings, we also found that IL-6 with or without sIL-6R could substantially increase STAT3 phosphorylation and expression of anti-apoptotic Mcl-1 protein in cultured IPAH PASMCs compared with control PASMCs. These effects were partially abolished in the presence of IL-6R neutralizing antibodies. Conclusions: Our findings suggest that abnormalities in IL-6 signaling may contribute to the pathogenesis of PAH through modulation of PASMC survival.