Abstract 12186: Therapeutic Effects of Blockade of IL-6/gp130 Signaling in Pulmonary Arterial Hypertension

• Published in: Circulation (New York, N.Y.) Vol. 132; no. Suppl_3 Suppl 3; p. A12186
• Main Authors: Tamura, Yuichi, Phan, Carole, Tu, Ly, Thuillet, Raphaël, Le Hiress, Morane, Huertas, Alice, Fadel, Elie, Simonneau, Gerald, Humbert, Marc, Guignabert, Christophe
• Format: Journal Article
• Language: English
• Published: by the American College of Cardiology Foundation and the American Heart Association, Inc 10.11.2015
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.132.suppl_3.12186

BackgroundInterleukin (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 still obscure.ObjectivesTo 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.MethodsWe 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 (PA-SMCs) of 10 controls and 10 idiopathic PAH (IPAH) patients. In addition, two complementary animal models of pulmonary hypertension (PH) have been studiedthe monocrotaline and SU5416 plus chronic hypoxia rat models.ResultsIn 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, p-STAT3 and myeloid leukemia-cell protein 1 (Mcl-1, a downstream target of IL-6) in the media of remodeled pulmonary arteries and cultured PA-SMCs 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 p-STAT3 and the anti-apoptotic Mcl-1 protein in cultured IPAH PA-SMCs compared with control cells. These effects were totally abolished in the presence of IL-6R neutralizing antibodies and an IL-6R antagonist. Finally, we found that daily treatment with IL-6R antagonist started 1 week after a subcutaneous monocrotaline injection substantially attenuates the abnormal increase in p-STAT3 and Mcl-1 and regresses established PH.ConclusionsWe demonstrate here that anti-IL-6R strategies may represent promising novels anti-proliferative and anti-inflammatory approaches for treatment of PAH.