ArticleProceedings of the National Academy of Sciences of the United States of America2015
Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 135 papers, 1 of them a synthesis that pooled it.
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Who cites it
135 citing papers in PubMed, 1 synthesis or guideline pooled it, 252 citations in OpenAlex.
- Pulmonary vascular involvement of IgG4-related disease: Case series with a PRISMA-compliant systemic review.Medicine · 2019Pooled it
- Beyond the Heart-Lung Axis: A Review of the Crosstalk Between the Hemodynamic, Neurohormonal, and Immune Systems in Pulmonary Hypertension.Comprehensive physiology · 2026Review
- Post-translational modification crosstalk in pulmonary arterial hypertension: mechanisms and therapeutic implications.Molecular biology reports · 2026Review
- Lactylation modification: a new bridge connecting macrophage metabolism and pulmonary hypertension.Applied microbiology and biotechnology · 2026Review
- Tetrahedral DNA Nanostructure-Based Biomimetic Nanovesicles Attenuate Sepsis-Associated ARDS by Suppressing Glycolysis via the BMAL1/PFKFB3 Axis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- R213G-Mediated Redistribution of EC-SOD Protects Against Sugen-Hypoxia Pulmonary Hypertension in Mice.Pulmonary circulation · 2026Article
- Endothelial USP2a-METTL16 loop potentiates IL-6 signaling via mCell death and differentiation · 2026Article
- SIRT5 Inhibits Mitophagy and Inflammation of Hypoxia-Induced Pulmonary Hypertension by Regulating the Desuccinylation of PDK1.Molecular biotechnology · 2026Article
- Chronic IL-21 exposure reshapes pulmonary environment, elevating risk of respiratory diseases.Cellular and molecular life sciences : CMLS · 2026Article
- Roles of the Altitude-Adapted Immune Microenvironment in Pulmonary Vascular Remodeling in High-Altitude Pulmonary Hypertension: A Review.Medical science monitor : international medical journal of experimental and clinical research · 2026Review
- PAH-former: Transfer learning for efficient discovery of pulmonary arterial hypertension-associated genes.PloS one · 2026Article
- Lactate and Lactylation in Pulmonary Hypertension: Comprehensive Landscape and Future Perspectives.International journal of medical sciences · 2026Review
- Role of connexin 43 in hyperoxia-induced bronchopulmonary dysplasia and associated pulmonary hypertension.PloS one · 2026Article
- IL-21-dependent Ly6CCell death discovery · 2025Article
- Pathophysiology of Pulmonary Arterial Hypertension: Focus on Vascular Endothelium as a Potential Therapeutic Target.International journal of molecular sciences · 2025Review
- Exploring the Impact of Platelet-Derived Growth Factor D in Pulmonary Hypertension Development.Pulmonary circulation · 2025Article
- Targeted Proteomic Analysis of Sickle Cell Disease Patients With Elevated Tricuspid Regurgitation Velocity.Proteomics. Clinical applications · 2025Article
- Novel and Highly Potent Therapeutic Agent, Trametes Robiniophila Murr (Huaier), Mitigates Pulmonary Vascular Remodeling in Rodents.Journal of the American Heart Association · 2025Article
- Oxidative Stress and Inflammation in Hypoxemic Respiratory Diseases and Their Comorbidities: Molecular Insights and Diagnostic Advances in Chronic Obstructive Pulmonary Disease and Sleep Apnea.Antioxidants (Basel, Switzerland) · 2025Review
- CTRP7 as a molecular biomarker associating with responsiveness to pulmonary vasodilators: insights from human and animal studies in pulmonary arterial hypertension.Cardiovascular research · 2025Article
75 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
19 authors at 7 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
IL-6 is a multifunctional proinflammatory cytokine that is elevated in the serum of patients with pulmonary arterial hypertension (PAH) and can predict the survival of patients with idiopathic PAH (IPAH). Previous animal experiments and clinical human studies indicate that IL-6 is important in PAH; however, the molecular mechanisms of IL-6-mediated pathogenesis of PAH have been elusive. Here we identified IL-21 as a downstream target of IL-6 signaling in PAH. First, we found that IL-6 blockade by the monoclonal anti-IL-6 receptor antibody, MR16-1, ameliorated hypoxia-induced pulmonary hypertension (HPH) and prevented the hypoxia-induced accumulation of Th17 cells and M2 macrophages in the lungs. Consistently, the expression levels of IL-17 and IL-21 genes, one of the signature genes for Th17 cells, were significantly up-regulated after hypoxia exposure in the lungs of mice treated with control antibody but not in the lungs of mice treated with MR16-1. Although IL-17 blockade with an anti-IL-17A neutralizing antibody had no effect on HPH, IL-21 receptor-deficient mice were resistant to HPH and exhibited no significant accumulation of M2 macrophages in the lungs. In accordance with these findings, IL-21 promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Of note, significantly enhanced expressions of IL-21 and M2 macrophage markers were detected in the lungs of IPAH patients who underwent lung transplantation. Collectively, these findings suggest that IL-21 promotes PAH in association with M2 macrophage polarization, downstream of IL-6-signaling. The IL-6/IL-21-signaling axis may be a potential target for treating PAH.
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