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Targeting IL-17 attenuates hypoxia-induced pulmonary hypertension through downregulation of β-catenin
  1. Lei Wang1,
  2. Jie Liu2,
  3. Wang Wang2,
  4. Xianmei Qi2,
  5. Ying Wang3,
  6. Bo Tian4,
  7. Huaping Dai1,
  8. Jing Wang5,
  9. Wen Ning6,
  10. Ting Yang1,
  11. Chen Wang1,7
  1. 1 Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Capital Medical University, Beijing, China
  2. 2 Department of Physiology and Pathophysiology, School of BasicMedical Sciences, Capital Medical University, Beijing, China
  3. 3 Department of Clinical Laboratory, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
  4. 4 Department of Thoracic Surgery, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
  5. 5 Department of Physiology and Pathophysiology, School of BasicMedical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
  6. 6 State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China
  7. 7 Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
  1. Correspondence to Professor Wen Ning, No.94, Weijin Road, Nankai District, Tianjin, China; ningwen108{at}nankai.edu.cn, Professor Ting Yang, No. 2, Yinghua Dong Road, ChaoYang District, Beijing, China; dryangting{at}qq.com and Professor Chen Wang, No. 9, Dongdan Santiao, Dong Cheng District, Beijing, China; cyh-birm{at}263.net

Abstract

Background The role of interleukin 17 (IL-17) in hypoxic pulmonary hypertension (HPH) remains unclear. This study is designed to explore whether IL-17 is a potential target for HPH treatment.

Methods Clinic samples from the lung tissue and serum were obtained from qualified patients. Western blotting, immunohistochemistry and/or ELISA were used to measure the expression of relevant proteins. HPH models were established in C57BL/6 wild-type (WT) and IL-17 −/− mice and were treated with exogenous recombinant mouse IL-17 (rmIL-17) or an IL-17 neutralising antibody. Assays for cell proliferation, angiogenesis and adhesion were employed to analyse the behaviours of human pulmonary arterial endothelial cells (HPAECs). A non-contact Transwell coculture model was used to evaluate intercellular interactions.

Results Expression of IL-17 was increased in lung tissue of both patients with bronchiectasis/COPD-associated PH and HPH mouse model. Compared with WT mice, IL-17 −/− mice had attenuated HPH, whereas administration of rmIL-17 aggravated HPH. In vitro, recombinant human IL-17 (rhIL-17) promoted proliferation, angiogenesis and adhesion in HPAECs through upregulation of Wnt3a/β-catenin/CyclinD1 pathway, and siRNA-mediated knockdown of β-catenin almost completely reversed this IL-17-mediated phenomena. IL-17 promoted the proliferation but not the migration of human pulmonary arterial smooth muscle cells (HPASMCs) cocultured with HPAECs under both normoxia and hypoxia, but IL-17 had no direct effect on proliferation and migration of HPASMCs. Blockade of IL-17 with a neutralising antibody attenuated HPH in WT mice.

Conclusions IL-17 contributes to the pathogenesis of HPH through upregulation of β-catenin expression. Targeting IL-17 might provide potential benefits for alternative therapeutic strategies for HPH.

  • hypoxia-induced pulmonary hypertension
  • IL-17
  • β-catenin
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Footnotes

  • Contributors LW participated in the design of the study, data acquisition, statistical analysis and drafting of the manuscript. JL, WW and XQ participated in acquisition of the data. YW participated in collecting serum samples. BT participated in collecting lung tissues from patients and donor. HD provided the IL-17 knockout mice and participated in the design of the study. JW participated in the design of the study and revised the manuscript. CW, TY and WN conceived of the study and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.

  • Funding This paper was supported by National Natural Science Foundation of China (81400039, 91643115 and 81470258).

  • Disclaimer Funding entities did not contribute to the study design or data collection, analysis and interpretation and the writing of the manuscript.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The study was approved by the Research Ethics Committee of Capital Medical University and Beijing Chao-Yang Hospital of Capital Medical University and China-Japan Friendship Hospital.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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