中文｜English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 40 Issue 11
Nov.  2024
Turn off MathJax
Article Contents
Article Navigation >  Journal of Clinical Hepatology  > 2024  >  40(11): 2229-2237

Effect of interleukin-22 on hepatic stellate cell activation and its mechanism

DOI: 10.12449/JCH241116

  • Department of Gastroenterology，Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University，Nanjing 210008，China

Research funding:

National Natural Science Foundation of China (81900552);

Nanjing Health Science and Technology Development Special Fund Project-Outstanding Youth Fund (JQX20005)

More Information
  • Corresponding author: ZHUGE Yuzheng， yuzheng9111963@aliyun.com （ORCID： 0000-0002-3829-5831）
  • Received Date: 2024-03-03
  • Accepted Date: 2024-05-17
  • Published Date: 2024-11-25
    Abstract
  •   Objective  To investigate the effect of interleukin-22 （IL-22） on the activation of hepatic stellate cells （HSCs） and its mechanism.  Methods  The human HSC LX-2 cells were selected for the study， and the LX-2 cells induced by TGF-β1 were used to establish a model of HSC activation. LX-2 cells were treated with IL-22 at gradient concentrations， and Western blot and qRT-PCR were used to measure the expression levels of the activation markers COL1A1 and α-SMA and determine the appropriate working concentration and time of the drug. Western blot， qRT-PCR， and immunofluorescence assay were used to determine the levels of Fn14 and the markers for endoplasmic reticulum stress （ERS） and activation in activated HSCs treated by IL-22. ERS in LX-2 cells was induced by tunicamycin （TM）， and Western blot and qRT-PCR were used to measure the levels of markers for ERS and activation in LX-2 cells treated by IL-22. TNF-like weak inducer of apoptosis （TWEAK） and small interfering RNA were used to upregulate and downregulate Fn14， and then the mRNA and protein expression levels of p-IRE1α， IRE1α， XBP1s， COL1A1， and α-SMA were measured. After LX-2 cells induced by TGF-β1 were treated by IL-22， TWEAK was used to upregulate Fn14， and Western blot and immunofluorescence assay were used to measure the levels of Fn14 and the markers for ERS and activation. The independent-samples t-test was used for comparison of continuous data between two groups； a one-way analysis of variance was used for comparison between multiple groups， and the Sidak’s multiple comparison test was used for further comparison between two groups.  Results  Compared with the TGF-β1 group， the TGF-β1+IL-22 group had significant reductions in the protein and mRNA expression levels of COL1A1 and α-SMA， with a more significant effect after treatment with 10 ng/mL IL-22 for 24 hours （all P<0.01）. Compared with the TGF-β1 group， the TGF-β1+IL-22 group had significant reductions in the expression levels of Fn14， p-IRE1α， and XBP1s （all P<0.05）. Compared with the TM group， the TM+IL-22 group had significant reductions in the expression levels of p-IRE1α， XBP1s， COL1A1， and α-SMA （all P<0.05）. Compared with the silenced control group， the Fn14 siRNA group had significant reductions in the expression levels of p-IRE1α， XBP1s， COL1A1， and α-SMA （all P<0.05）. Compared with the normal control group， the TWEAK group had significant increases in the expression levels of Fn14， p-IRE1α， XBP1s， COL1A1， and α-SMA （all P<0.01）. Compared with the TGFβ1+IL-22 group， the TGF-β1+IL-22+TWEAK group had significant increases in the expression levels of Fn14， p-IRE1α， XBP1s， COL1A1， and α-SMA （all P<0.05）.  Conclusion  IL-22 negatively regulates ERS in HSCs by inhibiting Fn14， thereby inhibiting the activation of HSCs.

     

    • FullText(HTML)
  • loading
    • References(30)
  • [1]
    GINÈS P, KRAG A, ABRALDES JG, et al. Liver cirrhosis[J]. Lancet, 2021, 398( 10308): 1359- 1376. DOI: 10.1016/s0140-6736(21)01374-x.
    [2]
    DEWIDAR B, MEYER C, DOOLEY S, et al. TGF-β in hepatic stellate cell activation and liver fibrogenesis-updated 2019[J]. Cells, 2019, 8( 11): 1419. DOI: 10.3390/cells8111419.
    [3]
    KISSELEVA T, BRENNER D. Molecular and cellular mechanisms of liver fibrosis and its regression[J]. Nat Rev Gastroenterol Hepatol, 2021, 18( 3): 151- 166. DOI: 10.1038/s41575-020-00372-7.
    [4]
    CROFT M, SIEGEL RM. Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases[J]. Nat Rev Rheumatol, 2017, 13( 4): 217- 233. DOI: 10.1038/nrrheum.2017.22.
    [5]
    WANG M, XIE ZJ, XU J, et al. TWEAK/Fn14 axis in respiratory diseases[J]. Clin Chim Acta, 2020, 509: 139- 148. DOI: 10.1016/j.cca.2020.06.007.
    [6]
    XU MC, ZHANG F, WANG AX, et al. Tumor necrosis factor-like weak inducer of apoptosis promotes hepatic stellate cells migration via canonical NF-‍κB/MMP9 pathway[J]. PLoS One, 2016, 11( 12): e0167658. DOI: 10.1371/journal.pone.0167658.
    [7]
    WANG AX, ZHANG F, XU H, et al. TWEAK/Fn14 promotes pro-inflammatory cytokine secretion in hepatic stellate cells via NF-κB/STAT3 pathways[J]. Mol Immunol, 2017, 87: 67- 75. DOI: 10.1016/j.molimm.2017.04.003.
    [8]
    LIU YM, VERMA VK, MALHI H, et al. Lipopolysaccharide downregulates macrophage-derived IL-22 to modulate alcohol-induced hepatocyte cell death[J]. Am J Physiol Cell Physiol, 2017, 313( 3): C305- C313. DOI: 10.1152/ajpcell.00005.2017.
    [9]
    KONG XN, FENG DC, WANG H, et al. Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice[J]. Hepatology, 2012, 56( 3): 1150- 1159. DOI: 10.1002/hep.25744.
    [10]
    LU DH, GUO XY, QIN SY, et al. Interleukin-22 ameliorates liver fibrogenesis by attenuating hepatic stellate cell activation and downregulating the levels of inflammatory cytokines[J]. World J Gastroenterol, 2015, 21( 5): 1531- 1545. DOI: 10.3748/wjg.v21.i5.1531.
    [11]
    ZHAO JJ, ZHANG Z, LUAN Y, et al. Pathological functions of interleukin-22 in chronic liver inflammation and fibrosis with hepatitis B virus infection by promoting T helper 17 cell recruitment[J]. Hepatology, 2014, 59( 4): 1331- 1342. DOI: 10.1002/hep.26916.
    [12]
    WU LY, LIU SH, LIU Y, et al. Up-regulation of interleukin-22 mediates liver fibrosis via activating hepatic stellate cells in patients with hepatitis C[J]. Clin Immunol, 2015, 158( 1): 77- 87. DOI: 10.1016/j.clim.2015.03.003.
    [13]
    YAP KN, YAMADA K, ZIKELI S, et al. Evaluating endoplasmic reticulum stress and unfolded protein response through the lens of ecology and evolution[J]. Biol Rev Camb Philos Soc, 2021, 96( 2): 541- 556. DOI: 10.1111/brv.12667.
    [14]
    JALAN R, CHIARA FD, BALASUBRAMANIYAN V, et al. Ammonia produces pathological changes in human hepatic stellate cells and is a target for therapy of portal hypertension[J]. J Hepatol, 2016, 64( 4): 823- 833. DOI: 10.1016/j.jhep.2015.11.019.
    [15]
    ZHU J, WANG RW, XU T, et al. Salvianolic acid A attenuates endoplasmic reticulum stress and protects against cholestasis-induced liver fibrosis via the SIRT1/HSF1 pathway[J]. Front Pharmacol, 2018, 9: 1277. DOI: 10.3389/fphar.2018.01277.
    [16]
    KIM RS, HASEGAWA D, GOOSSENS N, et al. The XBP1 arm of the unfolded protein response induces fibrogenic activity in hepatic stellate cells through autophagy[J]. Sci Rep, 2016, 6: 39342. DOI: 10.1038/srep39342.
    [17]
    HU ML, YANG SL, YANG L, et al. Interleukin-22 alleviated palmitate-induced endoplasmic reticulum stress in INS-1 cells through activation of autophagy[J]. PLoS One, 2016, 11( 1): e0146818. DOI: 10.1371/journal.pone.0146818.
    [18]
    GULHANE M, MURRAY L, LOURIE R, et al. High fat diets induce colonic epithelial cell stress and inflammation that is reversed by IL-22[J]. Sci Rep, 2016, 6: 28990. DOI: 10.1038/srep28990.
    [19]
    ROEHLEN N, CROUCHET E, BAUMERT TF. Liver fibrosis: Mechanistic concepts and therapeutic perspectives[J]. Cells, 2020, 9( 4): 875. DOI: 10.3390/cells9040875.
    [20]
    ZHOU X, WANG Z, HE XR, et al. Research advances in signaling pathways associated with potential anti-liver fibrosis drugs and targets[J]. J Clin Hepatol, 2023, 39( 12): 2932- 2941. DOI: 10.3969/j.issn.1001-5256.2023.12.027.

    周鑫, 王智, 何雪茹, 等. 潜在抗肝纤维化药物与靶点相关信号通路研究进展[J]. 临床肝胆病杂志, 2023, 39( 12): 2932- 2941. DOI: 10.3969/j.issn.1001-5256.2023.12.027.
    [21]
    WU Y, MIN J, GE C, et al. Interleukin 22 in liver injury, inflammation and cancer[J]. Int J Biol Sci, 2020, 16( 13): 2405- 2413. DOI: 10.7150/ijbs.38925.
    [22]
    EL-SHORBAGY AA, SHAFAA MW, SALAH ELBELTAGY R, et al. Liposomal IL-22 ameliorates liver fibrosis through miR-let7a/STAT3 signaling in mice[J]. Int Immunopharmacol, 2023, 124( Pt B): 111015. DOI: 10.1016/j.intimp.2023.111015.
    [23]
    MENG YX, HUO LJ. Role of interleukin-22 in the development and progression of liver fibrosis[J]. J Clin Hepatol, 2021, 37( 12): 2924- 2927. DOI: 10.3969/j.issn.1001-5256.2021.12.039.

    孟昱希, 霍丽娟. IL-22在肝纤维化发生发展中的作用[J]. 临床肝胆病杂志, 2021, 37( 12): 2924- 2927. DOI: 10.3969/j.issn.1001-5256.2021.12.039.
    [24]
    GUPTA RK, FUNG K, FIGUEROA DS, et al. Integrative keratinocyte responses to TWEAK with IL-13 and IL-22 reveal pathogenic transcriptomes associated with atopic dermatitis[J]. J Invest Dermatol, 2024, 144( 5): 1071- 1074. DOI: 10.1016/j.jid.2023.11.009.
    [25]
    NA M, YANG XB, DENG YK, et al. Endoplasmic reticulum stress in the pathogenesis of alcoholic liver disease[J]. PeerJ, 2023, 11: e16398. DOI: 10.7717/peerj.16398.
    [26]
    NAGAR P, SHARMA P, DHAPOLA R, et al. Endoplasmic reticulum stress in Alzheimer’s disease: Molecular mechanisms and therapeutic prospects[J]. Life Sci, 2023, 330: 121983. DOI: 10.1016/j.lfs.2023.121983.
    [27]
    ZARAFSHANI M, MAHMOODZADEH H, SOLEIMANI V, et al. Expression and clinical significance of IRE1-XBP1s, p62, and caspase-3 in colorectal cancer patients[J]. Iran J Med Sci, 2024, 49( 1): 10- 21. DOI: 10.30476/IJMS.2023.96922.2856.
    [28]
    LIU L, ZHAO ML, JIN X, et al. Adaptive endoplasmic reticulum stress signalling via IRE1α-XBP1 preserves self-renewal of haematopoietic and pre-leukaemic stem cells[J]. Nat Cell Biol, 2019, 21( 3): 328- 337. DOI: 10.1038/s41556-019-0285-6.
    [29]
    MAIERS JL, KOSTALLARI E, MUSHREF M, et al. The unfolded protein response mediates fibrogenesis and collagen I secretion through regulating TANGO1 in mice[J]. Hepatology, 2017, 65( 3): 983- 998. DOI: 10.1002/hep.28921.
    [30]
    ABDELFATTAH AM, MAHMOUD SS, EL-WAFAEY DI, et al. Diacerein ameliorates cholestasis-induced liver fibrosis in rat via modulating HMGB1/RAGE/NF-κB/JNK pathway and endoplasmic reticulum stress[J]. Sci Rep, 2023, 13( 1): 11455. DOI: 10.1038/s41598-023-38375-4.
    • Relative Articles
    • Supplements(0)
    • Cited By
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(4)  / Tables(1)

    Get Citation
    PDF
    XML

    Article Metrics

    Article views (100) PDF downloads(18) Cited by()
    Proportional views
    Related
        

    The first journal specializing in hepatobiliary and pancreatic diseases in China

    Supervisor：Ministry of Education of the People's Republic of China

    Sponsor：Jilin University

    Academic Support: Chinese Society of Hepatology，Chinese Medical Association

    Address: 461 Xinjiang Road, Changchun

    Submit：0431-88782044

    Peer review：0431-88783542

    Email：lcgdb@vip.163.com

    About Journal

    Submission Guideline

    Journal Online

    Hepatobiliary College

    Guidelines

    YesterdayIP[]YesterdayPV[]TodayIP[]TodayPV[]Online[]

    Website Design © 2020 Editorial Board of Journal of Clinical Hepatology 吉ICP备10000617号-1 Supported by: Beijing Renhe Information Technology Co. Ltd  

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return