褪黑素通过JNK/c-Jun信号通路抑制胆汁酸诱导Cxcl2表达的机制研究

谭雅; 唐菀; 徐子芊; 赵楠; 张晓珣; 柴进

doi:10.16016/j.2097-0927.202201199

您当前的位置：

首页 >

文章列表页 >

褪黑素通过JNK/c-Jun信号通路抑制胆汁酸诱导Cxcl2表达的机制研究

基础医学 | 更新时间：2026-01-09

- 褪黑素通过JNK/c-Jun信号通路抑制胆汁酸诱导Cxcl2表达的机制研究
- Melatonin inhibits bile acids-initiated Cxcl2 expression through JNK/c-Jun signalling pathway
- 陆军军医大学学报 2022年44卷第8期页码：782-788
- 作者机构：
  
  400038 重庆，陆军军医大学(第三军医大学)第一附属医院消化内科，代谢性肝病中心和胆汁淤积肝病中心
- 作者简介：
  
  [柴进，E-mail: jin.chai@cldcsw.org CHAI Jin, E-mail: jin.chai@cldcsw.org
- 基金信息：
  
  国家自然科学基金优秀青年科学基金(81922012);重庆市杰出青年科学基金(cstc2021jcyj-jqX0005)
- DOI：10.16016/j.2097-0927.202201199
  中图分类号： R575;R966;R977.1
- 收稿：2022-01-21，
  
  修回：2022-03-11，
  
  纸质出版：2022-04-30
- 稿件说明：
移动端阅览
谭雅, 唐菀, 徐子芊, 等. 褪黑素通过JNK/c-Jun信号通路抑制胆汁酸诱导Cxcl2表达的机制研究[J]. 陆军军医大学学报, 2022,44(8):782-788.

Ya TAN, Wan TANG, Ziqian XU, et al. Melatonin inhibits bile acids-initiated Cxcl2 expression through JNK/c-Jun signalling pathway[J]. Journal of Army Medical University, 2022, 44(8): 782-788.
谭雅, 唐菀, 徐子芊, 等. 褪黑素通过JNK/c-Jun信号通路抑制胆汁酸诱导Cxcl2表达的机制研究[J]. 陆军军医大学学报, 2022,44(8):782-788. DOI： 10.16016/j.2097-0927.202201199.

Ya TAN, Wan TANG, Ziqian XU, et al. Melatonin inhibits bile acids-initiated Cxcl2 expression through JNK/c-Jun signalling pathway[J]. Journal of Army Medical University, 2022, 44(8): 782-788. DOI： 10.16016/j.2097-0927.202201199.

摘要

目的

研究褪黑素抑制胆汁酸诱导趋化因子Cxcl2表达的分子调控机制。

方法

喂养小鼠含有1%胆酸(cholic acid，CA)的饲料2周，构建胆汁淤积小鼠模型，给予褪黑素腹腔注射(100 mg/kg，1次/d)。收集肝组织后HE染色，根据Scheuer系统进行病理组织学评分。采用Real-time qPCR及Western blot方法检测褪黑素对小鼠肝脏内Cxcl2、Cxcr2、Mpo、c-Jun表达的影响。使用免疫组化方法检测小鼠肝脏内c-Jun的表达。分离并培养小鼠原代肝细胞，使用结合型胆汁酸TCA联合褪黑素处理小鼠原代肝细胞，在体外水平进一步探索褪黑素抑制胆汁酸诱导的Cxcl2表达的机制。使用JNK激动剂Anisomycin和褪黑素共同处理小鼠原代肝细胞，检测趋化因子Cxcl2表达。

结果

褪黑素给药明显减轻胆汁淤积诱导的炎症性肝损伤(

0.05)。褪黑素明显抑制胆汁淤积小鼠肝脏内趋化因子Cxcl2及其受体Cxcr2表达，并抑制肝脏内中性粒细胞标志物Mpo和转录因子c-Jun的表达(

0.05)。褪黑素显著减少TCA诱导的小鼠原代肝细胞内趋化因子Cxcl2的表达(

0.05)。J

NK激动剂Anisomycin逆转褪黑素对Cxcl2的抑制作用(

0.05)。

结论

褪黑素通过抑制JNK/c-Jun信号通路来降低胆汁酸诱导的趋化因子Cxcl2表达。

Abstract

Objective

To investigate the underlying molecular mechanism by which melatonin suppresses bile acids (BAs)-initiated expression of chemokine C-X-C motif chemokine ligand 2 (Cxcl2).

Methods

Mice were fed a 1% cholic acid (CA)-supplemented diet for 2 weeks to establish a model of cholestatic disease

and were given an intraperitoneal injection of melatonin (100 mg/kg) once a day for 2 weeks. Then

the liver tissues were collected for HE staining

and the liver histology was scored using the Scheuer scoring system. Effects of melatonin on the expression of Cxcl2

Cxcr2

myeloperoxidase (Mpo) and c-Jun in the liver tissues at mRNA and protein levels were detected by real-time qPCR and Western blotting. The expression of c-Jun in the liver tissues was measured by immunohistochemical assay. Primary mouse hepatocytes were isolated and cultured

and then treated with taurine-conjugated bile acid

taurocholic acid (TCA) and melatonin in order to explore the mechanism of melatonin reducing BAs-initiated Cxcl2 expression. Furthermore

these primarily cultured cells were treated with anisomycin (JNK agonist) and melatonin to further detect the expression of Cxcl2.

Results

Melatonin treatment significantly ameliorated cholestasis-induced inflammatory liver injury (

0.05)

and reduced the elevated expression of Cxcl2

Cxcr2

Mpo(a biomarker of neutrophils) and the transcription factor c-Jun in the livers of cholestatic disease mice (

0.05). In addition

melatonin suppressed TCA-stimulated Cxcl2 in primary mouse hepatocytes (

0.05). Anisomycin reversed melatonin-inhibited Cxcl2 (

0.05).

Conclusion

Mela

tonin treatment can decrease BAs-initiated expression of Cxcl2

via

inhibition of JNK/c-Jun signaling pathway in mouse hepatocytes.

关键词

Keywords

references

CHIANG J Y L, FERRELL J M. Bile acids as metabolic regulators and nutrientsensors[J]. Annu Rev Nutr, 2019, 39: 175-200. DOI: 10.1146/annurev-nutr-082018-124344.

WAGNER M, ZOLLNER G, TRAUNER M. New molecular insights into the mechanisms ofcholestasis[J]. J Hepatol, 2009, 51(3): 565-580. DOI: 10.1016/j.jhep.2009.05.012.

CAI S Y, BOYER J L. The role of bile acids incholestatic liver injury[J]. Ann Transl Med, 2021, 9(8): 737. DOI: 10.21037/atm-20-5110.

QIN C C, LIU Y N, HU Y, et al . Macrophage inflammatory protein-2 as mediator of inflammation in acute liver injury[J ] . World J Gastroenterol, 2017, 23(17): 3043-3052. DOI: 10.3748/wjg.v23.i17.3043.

CAI S Y, OUYANG X S, CHEN Y L, et al . Bile acids initiatecholestatic liver injury by triggering a hepatocyte-specific inflammatory response[J ] . JCI Insight, 2017, 2(5): e90780. DOI: 10.1172/jci.insight.90780.

CIPOLLA-NETO J, AMARAL F G D. Melatonin as a hormone: new physiological and clinicalinsights[J]. Endocr Rev, 2018, 39(6): 990-1028. DOI: 10.1210/er.2018-00084.

GLASER S, HAN YY, FRANCIS H, et al . Melatonin regulation of biliary functions[J ] . Hepatobil Surg Nutr, 2014, 3(1): 35-43. DOI: 10.3978/j.issn.2304-3881.2013.10.04.

BAIOCCHI L, ZHOU T H, LIANGPUNSAKUL S, et al . Possible application of melatonin treatment in human diseases of the biliary tract[J ] . Am J Physiol Gastrointest Liver Physiol, 2019, 317(5): G651-G660. DOI: 10.1152/ajpgi.00110.2019.

CAI S Y, GAUTAM S, NGUYEN T, et al . ATP8B1 deficiency disrupts the bilecanalicular membrane bilayer structure in hepatocytes, but FXR expression and activity are maintained[J ] . Gastroenterology, 2009, 136(3): 1060-1069. DOI: 10.1053/j.gastro.2008.10.025.

CHAI J, CAI S Y, LIU X C, et al . Canalicular membrane MRP2/ABCC2 internalization is determined by Ezrin Thr567 phosphorylation in human obstructive cholestasis[J ] . J Hepatol, 2015, 63(6): 1440-1448. DOI: 10.1016/j.jhep.2015.07.016.

CHAI J, HE Y, CAI S Y, et al . Elevated hepatic multidrug resistance-associated protein 3/ATP-binding cassette subfamily C3 expression in human obstructive cholestasis is mediated through tumor necrosis factor alpha and c-Jun NH2-terminal kinase/stress-activated protein kinase-signaling pathway[J ] . Hepatology, 2012, 55(5): 1485-1494. DOI: 10.1002/hep.24801.

HARDELAND R. Melatonin and inflammation—Story of a double-edgedblade[J]. J Pineal Res, 2018, 65(4): e12525. DOI: 10.1111/jpi.12525.

WU N, MENG F Y, ZHOU T H, et al . Prolonged darkness reduces liver fibrosis in a mouse model of primarysclerosing cholangitis by miR-200b down-regulation[J ] . FASEB J, 2017, 31(10): 4305-4324. DOI: 10.1096/fj.201700097R.

ZHANG Y C, HONG J Y, ROCKWELL C E, et al . Effect of bile duct ligation on bile acid composition in mouse serum and liver[J ] . LiverInt, 2012, 32(1): 58-69. DOI: 10.1111/j.1478-3231.2011.02662.x.

ALLEN K, JAESCHKE H, COPPLE B L. Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructivecholestasis[J]. Am J Pathol, 2011, 178(1): 175-186. DOI: 10.1016/j.ajpath.2010.11.026.

LI M, CAI S Y, BOYER J L. Mechanisms of bile acid mediated inflammation in the liver[J]. Mol Aspects Med, 2017, 56: 45-53. DOI: 10.1016/j.mam.2017.06.001.

KONISHI T, SCHUSTER R M, GOETZMAN H S, et al . Cell-specific regulatory effects of CXCR2 oncholestatic liver injury[J ] . Am J Physiol Gastrointest Liver Physiol, 2019, 317(6): G773-G783. DOI: 10.1152/ajpgi.00080.2019.

LI J N, DAWSON P A. Animal models to study bile acidmetabolism[J]. Biochim Biophys Acta Mol Basis Dis, 2019, 1865(5): 895-911. DOI: 10.1016/j.bbadis.2018.05.011.

CAI S Y, GE M X, MENNONE A, et al . Inflammasome is activated in the liver of cholestatic patients and aggravates hepatic injury in bile duct-ligated mouse[J ] . Cell Mol Gastroenterol Hepatol, 2020, 9(4): 679-688. DOI: 10.1016/j.jcmgh.2019.12.008.

OH S, WOO J I, LIM D J, et al . ERK2-dependent activation of c-Jun is required fornontypeable Haemophilus influenzae-induced CXCL2 upregulation in inner ear fibrocytes[J ] . J Immunol, 2012, 188(7): 3496-3505. DOI: 10.4049/jimmunol.1103182.

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

褪黑素通过改善胆汁酸代谢减轻胆汁淤积肝损伤

线粒体转录因子A在婴儿胆汁淤积性黄疸肝细胞中的表达及其意义

阻塞性胆汁淤积中肝脏miR-200b-3p高表达对肝细胞的保护作用

BPDE诱导GC-1细胞凋亡及褪黑素的保护作用

基于转录组测序对胆汁酸诱导肝细胞反应的Hub基因的筛选及验证