Tregs-derived interleukin 35 attenuates endothelial proliferation through STAT1 in pulmonary hypertension

Naifu Wan; Wuwei Rong; Wentong Zhu; Daile Jia; Peiyuan Bai; Guizhu Liu; Qiangyou Wan; Ankang Lyu

doi:10.21037/atm-21-1952

Tregs-derived interleukin 35 attenuates endothelial proliferation through STAT1 in pulmonary hypertension

Ann Transl Med. 2021 Jun;9(11):926. doi: 10.21037/atm-21-1952.

Authors

Naifu Wan¹, Wuwei Rong¹, Wentong Zhu¹, Daile Jia², Peiyuan Bai², Guizhu Liu^{3

4}, Qiangyou Wan^{3

5}, Ankang Lyu¹

Affiliations

¹ Department of Vascular & Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
² Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
³ Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
⁴ State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
⁵ Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Abstract

Background: To explore the source, the role and the specific mechanism of IL-35 and its downstream molecules in the development of pulmonary hypertension.

Methods: 8-10 weeks male mice were undergoing hypoxia combined with SU5416 (HySu) to establish a pulmonary hypertension (PH) model. The phenotype of PH mice was measured by immunohistochemistry and immunofluorescence staining. The levels of two subunits (EBI3 and p35 subunits) in lung tissue were measured by real-time PCR and western blotting. EBI3 monoclonal antibody was administrated as IL-35 neutralization to offset systemic IL-35 expression. Fludarabine, an inhibitor of STAT1 (signal transducer and activator of transcription 1) was used to clarify the role of STAT1 under IL-35 treatment.

Results: After pulmonary hypertension, the expression of IL-35 and its two subunits (EBI3 and p35 subunits) in lung tissue were significantly increased. And the two subunits of IL-35 are highly expressed in Treg cells. Compared with the controlled PH mice, the IL-35 neutralization PH mice showed aggravated pulmonary hypertension phenotype. The specific manifestations are the increase of right ventricular systolic pressure (RVSP), the growing proportion of right heart [RV/(LV+S)], and the remodeling of pulmonary blood vessels increases. The expression of pulmonary vascular endothelium (CD31) in PH mice increased, and the proliferation ability of vascular endothelium enhanced after IL-35 was inhibited. IL-35 phosphorylates STAT1 through the receptor GP130 on pulmonary vascular endothelial cells, which in turn inhibits endothelial cell proliferation. IL-35 recombinant protein can reduce the expression of CD31 in lung tissues of PH mice. But the administration of STAT1 inhibitor made it invalid from the IL-35 effect of reversing pulmonary hypertension.

Conclusions: Tregs-derived IL-35 can reverse the remodeling of pulmonary blood vessels and alleviate the progression of pulmonary hypertension by reducing the proliferation of endothelial cells.

Keywords: Pulmonary hypertension (PH); cardiovascular disease.