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 still obscure. 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 (PA-SMCs) of 10 controls and 10 idiopathic PAH (IPAH) patients. In addition, two complementary animal models of pulmonary hypertension (PH) have been studied: the monocrotaline and SU5416 plus chronic hypoxia 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, 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. Conclusions: We demonstrate here that anti-IL-6R strategies may represent promising novels anti-proliferative and anti-inflammatory approaches for treatment of PAH.
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