PTP1B抑制肝纤维化逆转期TRAIL诱导的肝星状细胞凋亡

doi:10.5246/jcps.2023.11.070

中国药学(英文版) ›› 2023, Vol. 32 ›› Issue (11): 867-880.DOI: 10.5246/jcps.2023.11.070

PTP1B抑制肝纤维化逆转期TRAIL诱导的肝星状细胞凋亡

陈培杰¹^,²^,^*(), 张云天³^,⁴

1. 安徽医科大学第一附属医院, 药学部, 安徽合肥 230012
2. 安徽省公共卫生临床中心, 药学部, 安徽合肥 230012
3. 合肥晶合集成电路股份有限公司, 安徽合肥 230012
4. 中国科学技术大学现代力学系, 材料力学行为与设计重点实验室, 安徽合肥 230027

收稿日期:2023-03-24 修回日期:2023-05-12 接受日期:2023-06-08 出版日期:2023-12-02 发布日期:2023-12-02
通讯作者: 陈培杰
作者简介:
+ Tel.: +86-13615608319, E-mail: peijiechen@163.com
基金资助:
University Natural Science Research Project of Anhui Province (Grant No. KJ2020A0188); Foundation of Anhui Medical University (Grant No. 2019xkj055).

PTP1B restrains the apoptosis of activated hepatic stellate cells (HSCs) induced by TRAIL during the resolution of liver fibrosis

Peijie Chen¹^,²^,^*(), Yuntian Zhang³^,⁴

1 The First Affiliated Hospital of Anhui Medical University, Hefei 230012, Anhui, China
2 Anhui Public Health Clinical Center, Hefei 230012, Anhui, China
3 Hefei Jing-He Integrated Circuit Co., LTD, Hefei 230012, Anhui, China
4 CAS Key Laboratory of Mechanical Behavior and Design of Materials, Department of Modern Mechanics, University of Science and Technology of China, Hefei 230027, Anhui, China

Received:2023-03-24 Revised:2023-05-12 Accepted:2023-06-08 Online:2023-12-02 Published:2023-12-02
Contact: Peijie Chen

摘要/Abstract

摘要：

肝星状细胞(HSCs)的活化是肝纤维化病程进展中的核心环节。肝纤维化是一个可逆的病理过程, 去除病因后, 肝纤维化可以通过活化的HSCs凋亡和失活发生逆转。我们前期研究发现, 蛋白酪氨酸磷酸酶1B(PTP1B)在肝纤维化进展期和逆转恢复期, 可分别促进HSC活化和抑制aHSCs失活。但其在肝纤维化逆转期, 对活化的HSCs凋亡的作用尚不明确。为了探究PTP1B对aHSCs凋亡的影响, 本实验构建了小鼠肝纤维化及逆转模型; 体外培养了大鼠肝星状细胞系HSC-T6, TGF-β1刺激活化后给予TRAIL诱导其凋亡以模拟肝纤维化逆转期aHSC凋亡过程。结果显示, PTP1B在肝纤维化肝组织中表达上调, 而在纤维化自发恢复后表达降低。PTP1B在活化的HSC-T6中表达上调, 在凋亡的aHSCs中表达下降。此外, PTP1B抑制了TRAIL的肝纤维化缓解效应, 表现为过表达PTP1B后, TRAIL无法降低α-平滑肌肌动蛋白(α-SMA)及胶原蛋白的表达。同时, 过表达PTP1B可以抑制TRAIL诱导的细胞凋亡, 减少凋亡细胞的数量, 降低凋亡蛋白的表达及活性。研究表明, PTP1B可以通过影响aHSCs的凋亡参与肝纤维化的逆转。

关键词: 蛋白酪氨酸磷酸酶1B, 肝纤维化, 肝星状细胞, 肿瘤坏死因子相关凋亡诱导配体, 凋亡

Abstract:

The activation of hepatic stellate cells (HSCs) is a key event in hepatic fibrosis (HF). As a reversible progress, HF can be reversed by inactivation and apoptosis of activated HSCs (aHSCs). We previously found that protein tyrosine phosphatase 1B (PTP1B) promotes HSC activation and inhibits aHSCs inactivation during the progressive and recovery stages of HF. Nevertheless, the effect of PTP1B on apoptosis of aHSCs remains unknown. Therefore, we investigated the link between PTP1B and aHSCs apoptosis. Mouse liver fibrosis and reversal models were established for this purpose. After activated by transforming growth factor-β1 (TGF-β1), HSC-T6 cells were treated with TNF-related apoptosis-inducing ligand (TRAIL) to mimic apoptosis of aHSCs in vitro. The results showed that PTP1B was elevated in the fibrotic liver, but reduced after recovery. Consistently, PTP1B was highly-expressed in aHSCs, but declined in apoptotic aHSCs. Furthermore, PTP1B inhibited the alleviating effect of TRAIL in HF, indicating that TRAIL did not decrease collagen and α-smooth muscle actin (α-SMA) levels after PTP1B overexpression. Moreover, overexpression of PTP1B significantly restrained the pro-apoptotic effect of TRAIL, decreasing the number of apoptotic cells and apoptosis-related proteins. These observations revealed that PTP1B is involved in the reversal of HF by influencing the apoptosis of aHSCs.

Key words: Protein tyrosine phosphatase 1B, Liver fibrosis, Hepatic stellate cells, TNF-related apoptosis-inducing ligand, Apoptosis

Supporting:

陈培杰, 张云天. PTP1B抑制肝纤维化逆转期TRAIL诱导的肝星状细胞凋亡[J]. 中国药学(英文版), 2023, 32(11): 867-880.

Peijie Chen, Yuntian Zhang. PTP1B restrains the apoptosis of activated hepatic stellate cells (HSCs) induced by TRAIL during the resolution of liver fibrosis[J]. Journal of Chinese Pharmaceutical Sciences, 2023, 32(11): 867-880.

图/表 5

Table 1. Primers used in real-time PCR.

Figure 1. The expression of PTP1B in the livers from control, model and recovery groups, n = 12 per group. (A) Pathology observation of the experimental mouse liver sections stained with hematoxylin eosin (H&E) staining and Masson staining. Representative views from each group are presented (×100). (B) The expression of PTP1B and α-SMA were analyzed by immune-histochemistry in control, model, and recovery livers. Representative views from each group are presented (×100). (C) The levels of PTP1B, Col1α1, TRAIL and α-SMA protein were assessed by WB. The results are expressed as relative expression against negative control expression. Representative blots of three independent experiments are shown. **P < 0.01 vs control; ##P < 0.01 vs model.

Figure 2. The expression of PTP1B in HSC-T6 cells. (A) After exposure to TGF-β1, activated HSC-T6 cells were treated with TRAIL to induce apoptosis. The apoptosis of activated HSC-T6 cells were measured by flow cytometry. One representative experiment of the three independent experiments is demonstrated. #P < 0.05 vs TGF-β1. (B) The mRNA level of PTP1B, Col1α1 and α-SMA in apoptotic HSCs induced by TRAIL were examined by Real-time PCR, which was normalized using β-actin mRNA from each sample. *P < 0.05 vs control; **P < 0.01 vs control; #P < 0.05 vs TGF-β1, ##P < 0.01 vs TGF-β1. (C) The protein level of PTP1B, Col1α1 and α-SMA in apoptotic HSCs induced by TRAIL were assessed by WB. Representative blots of three independent experiments are presented. **P < 0.01 vs control; ##P < 0.01 vs TGF-β1.

Figure 3. The effect of PTP1B on the synthesis of extracellular matrix of HSC-T6 cells during TRAIL exposure. HSC-T6 cells activated by TGF-β1 were transfected with PTP1B or control plasmid to produce PTP1B-overexpressing and control cells, respectively. The cells were then treated with TRAIL to induce apoptosis. (A) The mRNA levels of PTP1B, Col1α1, and α-SMA in HSCs were examined by Real-time PCR and normalized using β-actin mRNA from each sample. **P < 0.01 vs TGF-β1; #P < 0.05 vs TGF-β1 + TRAIL + pEX3-control, ##P < 0.01 vs TGF-β1 + TRAIL + pEX3-control. (B) Protein levels of PTP1B, Col1α1, and α-SMA were assessed by WB. Representative blots from three independent experiments are presented. **P < 0.01 vs TGF-β1; #P < 0.05 vs TGF-β1 + TRAIL + pEX3-control, ##P < 0.01 vs TGF-β1 + TRAIL + pEX3-control.

Figure 4. The effect of PTP1B on TRAIL-induced apoptosis of activated HSC-T6 cells. Activated HSC-T6 cells induced by TGF-β1 were transfected with PTP1B or control plasmid to produce PTP1B-overexpressing and control cells, respectively. The cells were then treated with TRAIL to induce apoptosis. (A) Apoptosis of activated HSC-T6 cells was measured using flow cytometry. A representative experiment of three independent experiments is shown. **P < 0.01 vs TGF-β1; ##P < 0.01 vs TGF-β1 + TRAIL + pEX3-control. (B) The Caspase-3 activity was measured using a Caspase-3 activity assay kit, according to the manufacturer’s instructions. **P < 0.01 vs TGF-β1; ##P < 0.01 vs TGF-β1 + TRAIL + pEX3-control. (C) Levels of apoptosis-related proteins, including Caspase-3, Bax, and Bcl-2, were assessed by WB. Representative blots from three independent experiments are presented.

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PTP1B抑制肝纤维化逆转期TRAIL诱导的肝星状细胞凋亡

PTP1B restrains the apoptosis of activated hepatic stellate cells (HSCs) induced by TRAIL during the resolution of liver fibrosis

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