Skip to main content
SpringerLink
Log in

Inhibitory Effect of Emodin on Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) Expression in Rat Hepatic Stellate Cells

  • Basic Research
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Emodin inhibited expression of both transforming growth factor β1 (TGFβ1)- and phorbol ester (PMA)-induced tissue inhibitors of metalloproteinase-1 (TIMP-1) in an immortalized rat hepatic stellate cell line, HSC-T6, by Western blot and reverse transcription polymerase chain reaction. Reporter gene assays showed that emodin reduced both basal and PMA-induced activated protein-1 (AP-1) promoter activities. Electrophoretic mobility shift assay revealed that emodin reduced AP-1 DNA binding activities in HSC-T6 cells. AP-1 components analysis showed that emodin also attenuated JunD mRNA expression. Furthermore, emodin markedly inhibited TGFβ1-induced p42/p44 mitogen-activated protein kinase phosphorylation but did not alter PMA induction. We conclude that emodin effectively inhibits PMA- and TGFβ1-stimulated TIMP-1 expression in hepatic stellate cells by suppressing the AP-1 signaling pathway and extracellular signal-regulated kinase activation, respectively. These data provide new insight into the cellular and molecular mechanisms of emodin against liver fibrosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Olaso E, Friedman SL (1998) Molecular regulation of hepatic fibrogenesis. J Hepatol 29:836–847

    Article  PubMed  CAS  Google Scholar 

  2. Arthur MJ (2000) Fibrogenesis II. Metalloproteinases and their inhibitors in liver fibrosis. Am J Physiol Gastrointest Liver Physiol 279:G245–G249

    PubMed  CAS  Google Scholar 

  3. Murphy G, Docherty A (1992) The matrix metalloproteinases and their inhibitors. Am J Respir Cell Mol Biol 7:120–125

    PubMed  CAS  Google Scholar 

  4. Benyon RC, Iredale JP, Goddard S, Winwood PJ, Arthur MJ (1996) Expression of tissue inhibitor of metalloproteinases 1 and 2 is increased in fibrotic human liver. Gastroenterology 110:821–831

    Article  PubMed  CAS  Google Scholar 

  5. Herbst H, Wege T, Milani S, Pellegrini G, Orzechowski HD, Bechstein WO, Neuhaus P, Gressner AM, Schuppan D (1997) Tissue inhibitor of metalloproteinase-1 and -2 RNA expression in rat and human liver fibrosis. Am J Pathol 150:1647–1659

    PubMed  CAS  Google Scholar 

  6. Iredale JP, Benyon RC, Arthur MJ, Ferris WF, Alcolado R, Winwood PJ, Clark N, Murphy G (1996) Tissue inhibitor of metalloproteinase-1 messenger RNA expression is enhanced relative to interstitial collagenase messenger RNA in experimental liver injury and fibrosis. Hepatology 24:176–184

    Article  PubMed  CAS  Google Scholar 

  7. Benyon RC, Arthur MJ (2001) Extracellular matrix degradation and the role of hepatic stellate cells. Semin Liver Dis 21:373–384

    Article  PubMed  CAS  Google Scholar 

  8. Yoshiji H, Kuriyama S, Miyamoto Y, Thorgeirsson UP, Gomez DE, Kawata M, Yoshii J, Ikenaka Y, Noguchi R, Tsujinoue H, Nakatani T, Thorgeirsson SS, Fukui H (2000) Tissue inhibitor of metalloproteinases-1 promotes liver fibrosis development in a transgenic mouse model. Hepatology 32:1248–1254

    Article  PubMed  CAS  Google Scholar 

  9. Iredale JP, Benyon RC, Pickering J, McCullen M, Northrop M, Pawley S, Hovell C, Arthur MJ (1998) Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 102:538–549

    Article  PubMed  CAS  Google Scholar 

  10. Edwards DR, Leco KJ, Leco PA, Lim MS, Phillips BW, Raja J, Sharma R (2000) Regulation of TIMP gene expression. In: Hawkes SP, Edwards DR, Khokha R (eds) Tissue inhibitors of metalloproteinases in development and disease. Harwood Academic Press, Lausanne, Switzerland, pp 13–24

    Google Scholar 

  11. Bahr MJ, Vincent KJ, Arthur MJ, Fowler AV, Smart DE, Wright MC, Clark IM, Benyon RC, Iredale JP, Mann DA (1999) Control of the tissue inhibitor of metalloproteinases-1 promoter in culture-activated rat hepatic stellate cells: regulation by activator protein-1 DNA binding proteins. Hepatology 29:839–848

    Article  PubMed  CAS  Google Scholar 

  12. Smart DE, Vincent KJ, Arthur MJ, Eickelberg O, Castellazzi M, Mann J, Mann DA (2001) JunD regulates transcription of the tissue inhibitor of metalloproteinases-1 and interleukin-6 genes in activated hepatic stellate cells. J Biol Chem 276:24414–24421

    Article  PubMed  CAS  Google Scholar 

  13. Young DA, Billingham O, Sampieri CL, Edwards DR, Clark IM (2005) Differential effects of histone deacetylase inhibitors on phorbol ester- and TGF-beta1 induced murine tissue inhibitor of metalloproteinases-1 gene expression. FEBS J 272:1912–1926

    Article  PubMed  CAS  Google Scholar 

  14. Hall MC, Young DA, Waters JG, Rowan AD, Chantry A, Edwards DR, Clark IM (2003) The comparative role of activator protein 1 and Smad factors in the regulation of Timp-1 and MMP-1 gene expression by transforming growth factor-beta 1. J Biol Chem 278:10304–10313

    Article  PubMed  CAS  Google Scholar 

  15. Kuo YC, Tsai WJ, Meng HC, Chen WP, Yang LY, Lin CY (2001) Immune reponses in human mesangial cells regulated by emodin from Polygonum hypoleucum Ohwi. Life Sci 68:1271–1286

    Article  PubMed  CAS  Google Scholar 

  16. Kuo YC, Meng HC, Tsai WJ (2001) Regulation of cell proliferation, inflammatory cytokine production and calcium mobilization in primary human T lymphocytes by emodin from Polygonum hypoleucum Ohwi. Inflamm Res 50:73–82

    Article  PubMed  CAS  Google Scholar 

  17. Kumar A, Dhawan S, Aggarwal BB (1998) Emodin (3-methyl-1,6,8-trihydroxyanthraquinone) inhibits TNF-induced NF-kappaB activation, IkappaB degradation, and expression of cell surface adhesion proteins in human vascular endothelial cells. Oncogene 17:913–918

    Article  PubMed  CAS  Google Scholar 

  18. Chan TC, Chang CJ, Koonchanok NM, Geahlen RL (1993) Selective inhibition of the growth of ras-transformed human bronchial epithelial cells by emodin, a protein-tyrosine kinase inhibitor. Biochem Biophys Res Commun 193:1152–1158

    Article  PubMed  CAS  Google Scholar 

  19. Battistutta R, Sarno S, De Moliner E, Papinutto E, Zanotti G, Pinna LA (2000) The replacement of ATP by the competitive inhibitor emodin induces conformational modifications in the catalytic site of protein kinase CK2. J Biol Chem 275:29618–29622

    Article  PubMed  CAS  Google Scholar 

  20. Huang Q, Shen HM, Ong CN (2004) Inhibitory effect of emodin on tumor invasion through suppression of activator protein-1 and nuclear factor-kappaB. Biochem Pharmacol 68:361–371

    Article  PubMed  CAS  Google Scholar 

  21. Zhan Y, Li D, Wei H, Wang Z, Huang X, Xu Q, Lu H (2000) Emodin on hepatic fibrosis in rats. Chin Med J 113:599–601

    PubMed  CAS  Google Scholar 

  22. Imanishi Y, Maeda N, Otogawa K, Seki S, Matsui H, Kawada N, Arakawa T (2004) Herb medicine Inchin-ko-to (TJ-135) regulates PDGF-BB-dependent signaling pathways of hepatic stellate cells in primary culture and attenuates development of liver fibrosis induced by thioacetamide administration in rats. J Hepatol 41:242–250

    Article  PubMed  Google Scholar 

  23. Kim Y, Ratziu V, Choi SG, Lalazar A, Theiss G, Dang Q, Kim SJ (1998) Transcriptional activation of transforming growth factor beta1 and its receptors by the Kruppel-like factor Zf9/core promoter-binding protein and Sp1. Potential mechanisms for autocrine fibrogenesis in response to injury. J Biol Chem 273:33750–22758

    Article  PubMed  CAS  Google Scholar 

  24. Vogel S, Piantedosi R, Frank J, Lalazar A, Rockey DC, Friedman SL, Blaner WS (2000) An immortalized rat liver stellate cell line (HSC-T6): a new cell model for the study of retinoid metabolism in vitro. J Lipid Res 41:882–893

    PubMed  CAS  Google Scholar 

  25. Sharma RK, Pande V, Ramos MJ, Rajor HK, Chopra S, Meguro K, Inoue J, Otsuka M(2005) Inhibitory activity of polyhydroxycarboxylate chelators against recombinant NF-kappaB p50 protein-DNA binding. Bioorg Chem 33:67–81

    Article  PubMed  CAS  Google Scholar 

  26. Casini A, Pinzani M, Milani S, et al. (1993) Regulation of extracellular matrix synthesis by transforming growth factor beta 1 in human fat-storing cells. Gastroenterology 105:245–253

    PubMed  CAS  Google Scholar 

  27. Knittel T, Mehde M, Kobold D, Saile B, Dinter C, Ramadori G (1999) Expression patterns of matrix metalloproteinases and their inhibitors in parenchymal and non-parenchymal cells of rat liver: regulation by TNF-alpha and TGF-beta1. J Hepatol 30:48–60

    Article  PubMed  CAS  Google Scholar 

  28. Jeong DH, Lee SJ, Lee JH, Bae IH, Jeong KS, Jang JJ, Lim IK, Kim MR, Lee MJ, Lee YS (2001) Subcellular redistribution of protein kinase C isozymes is associated with rat liver cirrhotic changes induced by carbon tetrachloride or thioacetamide. J Gastroenterol Hepatol 16:34–40

    Article  PubMed  CAS  Google Scholar 

  29. Ramm GA, Li L, Britton RS, O’Neill R, Bacon BR(2003) Effect of protein kinase C activation and inhibition on rat hepatic stellate cell activation. Dig Dis Sci 48:790–796

    Article  PubMed  CAS  Google Scholar 

  30. Mucsi I, Skorecki KL, Goldberg HJ (1996) Extracellular signal-regulated kinase and the small GTP-binding protein, Rac, contribute to the effects of transforming growth factor-beta1 on gene expression. J Biol Chem 271:16567–16572

    Article  PubMed  CAS  Google Scholar 

  31. Reimann T, Hempel U, Krautwald S, Axmann A, Scheibe R, Seidel D, Wenzel KW (1997) Transforming growth factor-beta1 induces activation of Ras, Raf-1, MEK and MAPK in rat hepatic stellate cells. FEBS Lett 403:57–60

    Article  PubMed  CAS  Google Scholar 

  32. Su YT, Chang HL, Shyue SK, Hsu SL (2005) Emodin induces apoptosis in human lung adenocarcinoma cells through a reactive oxygen species-dependent mitochondrial signaling pathway. Biochem Pharmacol 70:229–241

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This work was financially supported by the National Natural Science Foundation of China (Grant No. 30171087).

Author information

Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, Second Military Medical University, Guo He Road 325, Shanghai 200433, PR China

    Min Gui, Yue Fan Zhang, Zhen Yu Xiao, Shuo Feng Wang, Yao Cheng Rui & Jun Ping Zhang

  2. State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai, PR China

    Jian Feng Dai

  3. Research Center for Marine Drugs, School of Pharmacy, Second Military Medical University, Shanghai, PR China

    Peng Sun

Authors
  1. Min Gui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yue Fan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhen Yu Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peng Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jian Feng Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shuo Feng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yao Cheng Rui
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jun Ping Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jun Ping Zhang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gui, M., Zhang, Y.F., Xiao, Z.Y. et al. Inhibitory Effect of Emodin on Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) Expression in Rat Hepatic Stellate Cells. Dig Dis Sci 52, 200–207 (2007). https://doi.org/10.1007/s10620-006-9321-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-006-9321-z

Keywords

Search

Navigation