ddr1诱导的肝细胞旁分泌因子促进HSC活化和纤维化发展。

IF 2.9 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Ying Meng, Tong Zhao, Tiyun Han, Huilin Chen, Zhengyi Zhang, Dekui Zhang
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引用次数: 0

摘要

背景:本研究旨在探讨盘状盘蛋白结构域受体-1 (DDR1)在肝纤维化过程中的作用及其潜在机制。方法:取小鼠血液和肝脏。在体外实验中,通过转染相应的慢病毒,构建了DDR1过表达(DDR1- oe)或DDR1敲低(DDR1- kd)的人正常肝细胞(LO2细胞系)和人肝癌细胞(HepG2细胞系)。人肝星状细胞(LX2细胞系)与上述稳定转染细胞经胶原处理的条件培养基(CM)孵育。收集细胞和上清液进行分子生化分析。结果:与野生型(WT)小鼠的正常肝脏相比,四氯化碳(CCL4)诱导的纤维化肝细胞中的DDR1表达增加。与ccl4处理的WT小鼠相比,ccl4处理的DDR1基因敲除(DDR1- ko)小鼠肝纤维化减轻,肝星状细胞(HSC)活化降低。LX2细胞在LO2 DDR1-OE细胞CM中培养,α-平滑肌肌动蛋白(αSMA)和I型胶原蛋白(COL1)表达增加,细胞增殖增加。同时,HepG2 DDR1-KD细胞CM培养的LX2细胞的细胞增殖能力下降,αSMA和COL1的表达水平下降。此外,DDR1-OE细胞CM中的IL6、TNFα和TGFβ1似乎通过NF-κB和Akt通路调控,促进LX2细胞的活化和增殖。结论:这些结果提示DDR1在肝细胞中促进HSC的活化和增殖,DDR1通过激活NF-κB和Akt通路诱导旁分泌因子IL6、TNFα和TGFβ1可能是其机制。我们的研究表明胶原受体DDR1可能是肝纤维化的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

DDR1-Induced Paracrine Factors of Hepatocytes Promote HSC Activation and Fibrosis Development.

DDR1-Induced Paracrine Factors of Hepatocytes Promote HSC Activation and Fibrosis Development.

Background: This study investigated the role and potential mechanisms of Discoidin domain receptors-1 (DDR1) during liver fibrogenesis.

Methods: Blood and livers were collected from mice. In the in vitro experiments, human normal hepatocyte (LO2 cell line) and human hepatoma cells (HepG2 cell line) with overexpressed DDR1 (DDR1-OE) or DDR1 knockdown (DDR1-KD) were constructed by transfecting the corresponding lentivirus. Human hepatic stellate cells (LX2 cell line) were incubated with a conditioned medium (CM) of the above stable transfected cells treated with collagen. The cells and supernatants were collected for molecular and biochemical analyses.

Results: DDR1 expression was increased in hepatocytes from carbon tetrachloride (CCL4)-induced fibrotic livers compared to normal livers in wild-type (WT) mice. Liver fibrosis was relieved, and hepatic stellate cells (HSC) activation was decreased in CCL4-treated DDR1 knockout (DDR1-KO) mice compared with CCL4-treated WT mice. LX2 cells cultured in CM of LO2 DDR1-OE cells revealed increased α-smooth muscle actin (αSMA) and type I collagen (COL1) expressions and cell proliferation. Meanwhile, cell proliferation and the expression levels of αSMA and COL1 in LX2 cells cultured in CM of HepG2 DDR1-KD cells were decreased. Moreover, IL6, TNFα, and TGFβ1 in CM of DDR1-OE cells appeared to promote LX2 cell activation and proliferation, regulated by NF-κB and Akt pathways.

Conclusion: These results indicated that DDR1 in hepatocytes promoted HSC activation and proliferation and that paracrine factors IL6, TNFα, and TGFβ1 induced by DDR1 through activating NF-κB and Akt pathways may be the underlying mechanisms. Our study suggests that collagen-receptor DDR1 may be a potential therapeutic target for hepatic fibrosis.

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来源期刊
Current molecular pharmacology
Current molecular pharmacology Pharmacology, Toxicology and Pharmaceutics-Drug Discovery
CiteScore
4.90
自引率
3.70%
发文量
112
期刊介绍: Current Molecular Pharmacology aims to publish the latest developments in cellular and molecular pharmacology with a major emphasis on the mechanism of action of novel drugs under development, innovative pharmacological technologies, cell signaling, transduction pathway analysis, genomics, proteomics, and metabonomics applications to drug action. An additional focus will be the way in which normal biological function is illuminated by knowledge of the action of drugs at the cellular and molecular level. The journal publishes full-length/mini reviews, original research articles and thematic issues on molecular pharmacology. Current Molecular Pharmacology is an essential journal for every scientist who is involved in drug design and discovery, target identification, target validation, preclinical and clinical development of drugs therapeutically useful in human disease.
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