• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

TIMP-1通过诱导Fli-1促进实验性肝纤维化中MCP-1的表达和巨噬细胞迁移。

TIMP-1 Promotes Expression of MCP-1 and Macrophage Migration by Inducing Fli-1 in Experimental Liver Fibrosis.

作者信息

Huang Xiaoli, Wang Xiaofan, Wang Yanhong, Shen Shuangjun, Chen Wei, Liu Tianhui, Wang Ping, Fan Xu, Liu Lin, Jia Jidong, Cong Min

机构信息

Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.

Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China.

出版信息

J Clin Transl Hepatol. 2024 Jul 28;12(7):634-645. doi: 10.14218/JCTH.2023.00514. Epub 2024 Jun 11.

DOI:10.14218/JCTH.2023.00514
PMID:38993513
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11233975/
Abstract

BACKGROUND AND AIMS

Tissue inhibitor of metalloproteinase-1 (TIMP-1) plays a role in the excessive generation of extracellular matrix in liver fibrosis. This study aimed to explore the pathways through which TIMP-1 controls monocyte chemoattractant protein-1 (MCP-1) expression and promotes hepatic macrophage recruitment.

METHODS

Liver fibrosis was triggered through carbon tetrachloride, and an adeno-associated virus containing small interfering RNA targeting TIMP-1 (siRNA-TIMP-1) was administered to both rats and mice. We assessed the extent of fibrosis and macrophage recruitment. The molecular mechanisms regulating macrophage recruitment by TIMP-1 were investigated through transwell migration assays, luciferase reporter assays, the use of pharmacological modulators, and an analysis of extracellular vesicles (EVs).

RESULTS

siRNA-TIMP-1 alleviated carbon tetrachloride-induced liver fibrosis, reducing macrophage migration and MCP-1 expression. Co-culturing macrophages with hepatic stellate cells (HSCs) post-TIMP-1 downregulation inhibited macrophage migration. In siRNA-TIMP-1-treated HSCs, microRNA-145 (miRNA-145) expression increased, while the expression of Friend leukemia virus integration-1 (Fli-1) and MCP-1 was inhibited. Downregulation of Fli-1 led to decreased MCP-1 expression, whereas Fli-1 overexpression increased MCP-1 expression within HSCs. Transfection with miRNA-145 mimics reduced the expression of both Fli-1 and MCP-1, while miRNA-145 inhibitors elevated the expression of both Fli-1 and MCP-1 in HSCs. miRNA-145 bound directly to the 3'-UTR of Fli-1, and miRNA-145-enriched EVs secreted by HSCs after TIMP-1 downregulation influenced macrophage recruitment.

CONCLUSIONS

TIMP-1 induces Fli-1 expression through miRNA-145, subsequently increasing MCP-1 expression and macrophage recruitment. MiRNA-145-enriched EVs from HSCs can transmit biological information and magnify the function of TIMP-1.

摘要

背景与目的

金属蛋白酶组织抑制剂-1（TIMP-1）在肝纤维化过程中细胞外基质过度生成方面发挥作用。本研究旨在探索TIMP-1调控单核细胞趋化蛋白-1（MCP-1）表达并促进肝巨噬细胞募集的途径。

方法

通过四氯化碳诱导肝纤维化，对大鼠和小鼠给予携带靶向TIMP-1的小干扰RNA的腺相关病毒（siRNA-TIMP-1）。我们评估了纤维化程度和巨噬细胞募集情况。通过Transwell迁移试验、荧光素酶报告试验、使用药理学调节剂以及细胞外囊泡（EV）分析，研究了TIMP-1调控巨噬细胞募集的分子机制。

结果

siRNA-TIMP-1减轻了四氯化碳诱导的肝纤维化，减少了巨噬细胞迁移和MCP-1表达。TIMP-1下调后，将巨噬细胞与肝星状细胞（HSC）共培养可抑制巨噬细胞迁移。在经siRNA-TIMP-1处理的HSC中，微小RNA-145（miRNA-145）表达增加，而Friend白血病病毒整合-1（Fli-1）和MCP-1的表达受到抑制。Fli-1下调导致MCP-1表达降低，而Fli-1过表达则增加了HSC内MCP-1的表达。用miRNA-145模拟物转染可降低Fli-1和MCP-1的表达，而miRNA-145抑制剂则提高了HSC中Fli-1和MCP-1的表达。miRNA-145直接与Fli-1的3'-非翻译区结合，TIMP-1下调后HSC分泌的富含miRNA-145的EV影响巨噬细胞募集。

结论

TIMP-1通过miRNA-145诱导Fli-1表达，随后增加MCP-1表达和巨噬细胞募集。来自HSC的富含miRNA-145的EV可传递生物信息并放大TIMP-1的功能。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/539d/11233975/4e4020d7b2b1/JCTH-12-634-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/539d/11233975/8d5b068f4bc4/JCTH-12-634-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/539d/11233975/96905b8e2b30/JCTH-12-634-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/539d/11233975/1bfb96ccf1e1/JCTH-12-634-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/539d/11233975/fbe3645166be/JCTH-12-634-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/539d/11233975/1d28ebdd1de7/JCTH-12-634-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/539d/11233975/4e4020d7b2b1/JCTH-12-634-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/539d/11233975/8d5b068f4bc4/JCTH-12-634-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/539d/11233975/96905b8e2b30/JCTH-12-634-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/539d/11233975/1bfb96ccf1e1/JCTH-12-634-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/539d/11233975/fbe3645166be/JCTH-12-634-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/539d/11233975/1d28ebdd1de7/JCTH-12-634-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/539d/11233975/4e4020d7b2b1/JCTH-12-634-g006.jpg

相似文献

1
TIMP-1 Promotes Expression of MCP-1 and Macrophage Migration by Inducing Fli-1 in Experimental Liver Fibrosis.TIMP-1通过诱导Fli-1促进实验性肝纤维化中MCP-1的表达和巨噬细胞迁移。
J Clin Transl Hepatol. 2024 Jul 28;12(7):634-645. doi: 10.14218/JCTH.2023.00514. Epub 2024 Jun 11.
2
Antifibrotic effects of a recombinant adeno-associated virus carrying small interfering RNA targeting TIMP-1 in rat liver fibrosis.携带靶向 TIMP-1 的小干扰 RNA 的重组腺相关病毒对大鼠肝纤维化的抗纤维化作用。
Am J Pathol. 2013 May;182(5):1607-16. doi: 10.1016/j.ajpath.2013.01.036. Epub 2013 Mar 7.
3
MicroRNA-30a ameliorates hepatic fibrosis by inhibiting Beclin1-mediated autophagy.微小 RNA-30a 通过抑制 Beclin1 介导的自噬来改善肝纤维化。
J Cell Mol Med. 2017 Dec;21(12):3679-3692. doi: 10.1111/jcmm.13278. Epub 2017 Aug 1.
4
Suppression of tissue inhibitor of metalloproteinase-1 by recombinant adeno-associated viruses carrying siRNAs in hepatic stellate cells.携带小干扰RNA的重组腺相关病毒对肝星状细胞中金属蛋白酶组织抑制因子-1的抑制作用
Int J Mol Med. 2009 Nov;24(5):685-92. doi: 10.3892/ijmm_00000280.
5
Adiponectin reduces hepatic stellate cell migration by promoting tissue inhibitor of metalloproteinase-1 (TIMP-1) secretion.脂联素通过促进金属蛋白酶组织抑制剂-1（TIMP-1）的分泌来减少肝星状细胞迁移。
J Biol Chem. 2015 Feb 27;290(9):5533-42. doi: 10.1074/jbc.M114.598011. Epub 2015 Jan 9.
6
CCR2 promotes hepatic fibrosis in mice.CCR2可促进小鼠肝纤维化。
Hepatology. 2009 Jul;50(1):185-97. doi: 10.1002/hep.22952.
7
Hepatic stellate cell autophagy inhibits extracellular vesicle release to attenuate liver fibrosis.肝星状细胞自噬抑制细胞外囊泡释放以减轻肝纤维化。
J Hepatol. 2020 Nov;73(5):1144-1154. doi: 10.1016/j.jhep.2020.04.044. Epub 2020 May 8.
8
Modified synthetic siRNA targeting tissue inhibitor of metalloproteinase-2 inhibits hepatic fibrogenesis in rats.靶向金属蛋白酶组织抑制剂-2的改良合成小干扰RNA抑制大鼠肝纤维化形成。
J Gene Med. 2007 Mar;9(3):217-29. doi: 10.1002/jgm.1009.
9
Placental growth factor silencing ameliorates liver fibrosis and angiogenesis and inhibits activation of hepatic stellate cells in a murine model of chronic liver disease.沉默胎盘生长因子可改善慢性肝病小鼠模型的肝纤维化和血管生成，并抑制肝星状细胞的活化。
J Cell Mol Med. 2017 Oct;21(10):2370-2385. doi: 10.1111/jcmm.13158. Epub 2017 Apr 5.
10
MicroRNA-98 Inhibits Hepatic Stellate Cell Activation and Attenuates Liver Fibrosis by Regulating HLF Expression.微小RNA-98通过调节肝白血病因子表达抑制肝星状细胞活化并减轻肝纤维化。
Front Cell Dev Biol. 2020 Jun 19;8:513. doi: 10.3389/fcell.2020.00513. eCollection 2020.

引用本文的文献

1
Extracellular Vesicles from Adipose-Derived Mesenchymal Stem Cells Improve Ligament-Bone Integration After Anterior Cruciate Ligament Primary Repair in Rabbit.脂肪来源间充质干细胞分泌的细胞外囊泡改善兔前交叉韧带初次修复后的韧带-骨整合
Biomolecules. 2025 Mar 10;15(3):396. doi: 10.3390/biom15030396.
2
Cigarette Smoke Contributes to the Progression of MASLD: From the Molecular Mechanisms to Therapy.香烟烟雾促进代谢相关脂肪性肝病的进展：从分子机制到治疗
Cells. 2025 Feb 4;14(3):221. doi: 10.3390/cells14030221.
3
Pericytes mediate neuroinflammation via Fli-1 in endotoxemia and sepsis in mice.

本文引用的文献

1
Aldehyde dehydrogenase 2-mediated aldehyde metabolism promotes tumor immune evasion by regulating the NOD/VISTA axis.醛脱氢酶 2 介导的醛代谢通过调节 NOD/VISTA 轴促进肿瘤免疫逃逸。
J Immunother Cancer. 2023 Dec 7;11(12):e007487. doi: 10.1136/jitc-2023-007487.
2
Ginsenoside Rh4 inhibits inflammation-related hepatocellular carcinoma progression by targeting HDAC4/IL-6/STAT3 signaling.人参皂苷 Rh4 通过靶向 HDAC4/IL-6/STAT3 信号通路抑制炎症相关的肝细胞癌进展。
Mol Genet Genomics. 2023 Nov;298(6):1479-1492. doi: 10.1007/s00438-023-02070-w. Epub 2023 Oct 16.
3
Roles of Matrix Metalloproteinases and Their Natural Inhibitors in Metabolism: Insights into Health and Disease.
在小鼠内毒素血症和脓毒症中，周细胞通过Fli-1介导神经炎症。
Inflamm Res. 2025 Jan 25;74(1):28. doi: 10.1007/s00011-025-02000-z.
基质金属蛋白酶及其天然抑制剂在代谢中的作用：健康与疾病的新视角。
Int J Mol Sci. 2023 Jun 26;24(13):10649. doi: 10.3390/ijms241310649.
4
The Global Burden of Liver Disease.《全球肝脏疾病负担》
Clin Gastroenterol Hepatol. 2023 Jul;21(8):1978-1991. doi: 10.1016/j.cgh.2023.04.015. Epub 2023 Apr 28.
5
Matrix metalloproteinases induce extracellular matrix degradation through various pathways to alleviate hepatic fibrosis.基质金属蛋白酶通过多种途径诱导细胞外基质降解，从而减轻肝纤维化。
Biomed Pharmacother. 2023 May;161:114472. doi: 10.1016/j.biopha.2023.114472. Epub 2023 Mar 2.
6
A review of the effect of exosomes from different cells on liver fibrosis.不同细胞来源外泌体对肝纤维化影响的综述
Biomed Pharmacother. 2023 May;161:114415. doi: 10.1016/j.biopha.2023.114415. Epub 2023 Feb 20.
7
An iron-dependent form of non-canonical ferroptosis induced by labile iron.一种由不稳定铁诱导的铁依赖性非典型铁死亡形式。
Sci China Life Sci. 2023 Mar;66(3):516-527. doi: 10.1007/s11427-022-2244-4. Epub 2022 Dec 9.
8
Intracellular labile iron is a key regulator of hepcidin expression and iron metabolism.细胞内可利用铁是调节铁调素表达和铁代谢的关键。
Hepatol Int. 2023 Jun;17(3):636-647. doi: 10.1007/s12072-022-10452-2. Epub 2022 Dec 13.
9
Aberrant iron distribution via hepatocyte-stellate cell axis drives liver lipogenesis and fibrosis.异常的铁分布通过肝细胞-星状细胞轴驱动肝脏脂肪生成和纤维化。
Cell Metab. 2022 Aug 2;34(8):1201-1213.e5. doi: 10.1016/j.cmet.2022.07.006.
10
Mesenchymal stem cells improve liver fibrosis and protect hepatocytes by promoting microRNA-148a-5p-mediated inhibition of Notch signaling pathway.间充质干细胞通过促进 microRNA-148a-5p 介导的 Notch 信号通路抑制来改善肝纤维化并保护肝细胞。
Stem Cell Res Ther. 2022 Jul 26;13(1):354. doi: 10.1186/s13287-022-03030-8.