Lei Wang 1 , Jie Liu 2 , Wang Wang 2 , Xianmei Qi 2 , Ying Wang 3 , Bo Tian 4 , Huaping Dai 1 , Jing Wang 5 , Wen Ning 6 , Ting Yang 1 , Chen Wang 1,7 Show Affiliations »
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. © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
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. © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
Entities: Chemical
Disease
Gene
Species
Keywords:
IL-17; hypoxia-induced pulmonary hypertension; β-catenin
Mesh： See more »
Substances： See more »
Year: 2019
PMID： 30777899 DOI： 10.1136/thoraxjnl-2018-211846
Source DB: PubMed Journal: Thorax ISSN： 0040-6376 Impact factor: 9.139