Tregs-derived interleukin 35 attenuates endothelial proliferation through STAT1 in pulmonary hypertension.
Tregs-derived interleukin 35 attenuates endothelial proliferation through STAT1 in pulmonary hypertension.
复制标题
Tregs 衍生的白细胞介素 35 通过 STAT1 减弱肺动脉高压中的内皮增殖
DOI：
10.21037/atm-21-1952
复制
发表时间：
2021-06
影响因子：
--
通讯作者：
Lyu A
中科院分区：
文献类型：
--
作者：
Wan N;Rong W;Zhu W;Jia D;Bai P;Liu G;Wan Q;Lyu A
探讨IL-35及其下游分子在肺动脉高压发生发展中的来源、作用及具体机制。8~10周龄雄性小鼠采用低氧复合苏维素5416(HySu)建立肺动脉高压(PH)模型。免疫组织化学和免疫荧光染色检测PH小鼠的表型。实时荧光定量聚合酶链式反应和免疫印迹法检测肺组织中EBI3和p35亚基的表达水平。给予EBI3单抗作为IL-35的中和剂，以抵消系统IL-35的表达。用信号转导和转录激活因子1(STAT1)的抑制剂氟达拉滨来阐明信号转导和转录激活因子1在IL-35作用下的作用。肺动脉高压后，肺组织中IL-35及其两个亚单位EBI3和p35亚基的表达显著增加。IL-35的两个亚基在Treg细胞中高表达。与对照组相比，IL-35中和的PH小鼠表现出更严重的肺动脉高压表型。具体表现为右室收缩压升高，右心比例增大[RV/(LV+S)]，肺血管重塑增加。IL-35抑制后，肺血管内皮细胞(CD31)表达增加，血管内皮细胞增殖能力增强。IL-35通过肺血管内皮细胞上的受体gp130磷酸化STAT1，进而抑制内皮细胞的增殖。IL-35重组蛋白可降低肺组织中CD31的表达。但STAT1抑制剂的应用使IL-35逆转肺动脉高压的作用失效。Tregs来源的IL-35可通过抑制内皮细胞的增殖，逆转肺血管重塑，减缓肺动脉高压的进展。
To explore the source, the role and the specific mechanism of IL-35 and its downstream molecules in the development of pulmonary hypertension. 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. 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. 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.
登录
查看更多内容
影响因子：
16.6
作者：
Lee CC;Lin JC;Hwang WL;Kuo YJ;Chen HK;Tai SK;Lin CC;Yang MH
通讯作者：
Yang MH
DOI：
10.1164/rccm.201709-1835oc
发表时间：
2018-09-15
影响因子：
24.7
作者：
Dai, Zhiyu;Zhu, Maggie M.;Zhao, You-Yang
通讯作者：
Zhao, You-Yang
影响因子：
37.8
作者：
Hopper RK;Moonen JR;Diebold I;Cao A;Rhodes CJ;Tojais NF;Hennigs JK;Gu M;Wang L;Rabinovitch M
通讯作者：
Rabinovitch M
白介素 35 表达与胰腺导管腺癌中的微血管密度相关，募集单核细胞并促进小鼠异种移植肿瘤的生长和血管生成。
影响因子：
29.4
作者：
Huang, Chongbiao;Li, Zengxun;Ren, He
通讯作者：
Ren, He
影响因子：
20.1
作者：
Calvier, Laurent;Boucher, Philippe;Hansmann, Georg
通讯作者：
Hansmann, Georg