Abstract
Aim:
Epigallocatechin-3-gallate (EGCG) is the major component of green tea polyphenols, whose wide range of biological properties includes anti-fibrogenic activity. Matrix metalloproteinases (MMP) that participate in extracellular matrix degradation are involved in the development of hepatic fibrosis. The present study investigates whether EGCG inhibits activation of the major gelatinase matrix metalloproteinase-2 (MMP-2) in rat hepatic stellate cells (HSC).
Methods:
The expression of MMP-2, tissue inhibitors of metalloproteinases-2 (TIMP-2), and membrane-type 1-MMP (MT1-MMP) was assessed by RT-PCR and Western blot analyses. MMP-2 activity was evaluated by zymography and MT1-MMP activity was assessed by an enzymatic assay. HSC migration was measured by a wound healing assay and cell invasion was performed using Transwell cell culture chambers.
Results:
The expression of MMP-2 mRNA and protein in HSC was substantially reduced by EGCG treatment. EGCG treatment also reduced con-canavalin A (ConA)-induced activation of secreted MMP-2 and reduced MT1-MMP activity in a dose-dependent manner. In addition, EGCG inhibited either HSC migration or invasion.
Conclusion:
The abilities of EGCG to suppress MMP-2 activation and HSC invasiveness suggest that EGCG may be useful in the treatment and prevention of hepatic fibrosis.
Similar content being viewed by others
Article PDF
References
Friedman SL . Liver fibrosis-from bench to bedside. J Hepatol 2003; 38: S38–53.
Geerts A . History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin Liver Dis 2001; 21: 311–35.
Friedman SL, Bansal MB . Reversal of hepatic fibrosis — fact or fantasy? Hepatology 2006; 43: S82–8.
Preaux AM, Mallat A, Nhieu JT, D'Ortho MP, Hembry RM, Mavier P . Matrix metalloproteinase-2 activation in human hepatic fibrosis by cell-matrix interaction. Hepatology 1999; 30: 944–50.
Benyon RC, Arthur MJ . Extracellular matrix degradation and the role of hepatic stellate cells. Semin Liver Dis 2001; 21: 373–84.
Gaca MD, Zhou X, Issa R, Kiriella K, Iredale JP, Benyon RC . Basement membrane-like matrix inhibits proliferation and collagen synthesis by activated rat hepatic stellate cells: evidence for matrix-dependent deactivation of stellate cells. Matrix Biol 2003; 22: 229–39.
Visse R, Nagase H . Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 2003; 92: 827–39.
Fridman R . Surface association of secreted matrix metalloproteinases. Curr Top Dev Biol 2003; 54: 75–100.
Preaux AM, Mallat A, Nhieu JT, D'Ortho MP, Hembry RM, Mavier P . Matrix metalloproteinase-2 activation in human hepatic fibrosis by cell-matrix interaction. Hepatology 1999; 30: 944–50.
Parola M, Robino G . Oxidative stress-related molecules and liver fibrosis. J Hepatol 2001; 35: 297–306.
Galli A, Svegliati-Baroni G, Ceni E, Milani S, Ridolfi F, Salzano R, et al. Oxidative stress stimulates proliferation and invasiveness of hepatic stellate cells via a MMP2-mediated mechanism. Hepatology 2005; 41: 1074–84.
Migita K, Maeda Y, Abiru S, Komori A, Yokoyama T, Takii Y, et al. Peroxynitrite-mediated matrix metalloproteinase-2 activation in human hepatic stellate cells. FEBS Lett 2005; 579: 3119–25.
Gardi C, Arezzini B, Fortino V, Comporti M . Effect of free iron on collagen synthesis, cell proliferation and MMP-2 expression in rat hepatic stellate cells. Biochem Pharmacol 2002; 64: 1139–45.
Hendrich AB . Flavonoid-membrane interactions: possible consequences for biological effects of some polyphenolic compounds. Acta Pharmacol Sin 2006; 27: 27–40.
El Bedoui J, Oak MH, Anglard P, Schini-Kerth VB . Catechins prevent vascular smooth muscle cell invasion by inhibiting MT1-MMP activity and MMP-2 expression. Cardiovasc Res 2005; 67: 317–25.
Dona M, Dell'Aica I, Calabrese F, Benelli R, Morini M, Albini A, et al. Neutrophil restraint by green tea: inhibition of inflammation, associated angiogenesis, and pulmonary fibrosis. J Immunol 2003; 170: 4335–41.
Hung CF, Huang TF, Chiang HS, Wu WB . (-)-Epigallocatechin-3-gallate, a polyphenolic compound from green tea, inhibits fibroblast adhesion and migration through multiple mechanisms. J Cell Biochem 2005; 96: 183–97.
Mart HP, McNeil L, Davies M, Martin J, Lovett DH . Homology cloning of rat 72 kDa type IV collagenase: cytokine and second-messenger inducibility in glomerular mesangial cells. Biochem J 1993; 15: 441–6.
Okada A, Bellocq JP, Rouyer N, Chenard MP, Rio MC, Chambon P, et al. Membrane-type matrix metalloproteinase (MT-MMP) gene is expressed in stromal cells of human colon, breast, and head and neck carcinomas. Proc Natl Acad Sci USA 1995; 28: 2730–4.
Cook F, Burke JS, Bergman KD, Quinn CO, Jeffrey JJ, Partridge NC . Cloning and regulation of rat tissue inhibitor of metalloproteinases-2 in osteoblastic cells. Arch Biochem Biophys 1994; 311: 313–20.
Valster A, Tran NL, Nakada M, Berens ME, Chan AY, Symons M . Cell migration and invasion assays. Methods 2005; 37: 208–15.
Theret N, Lehti K, Musso O, Clement B . MMP2 activation by collagen I and concanavalin A in cultured human hepatic stellate cells. Hepatology 1999; 30: 462–8.
Benyon RC, Hovell CJ, Da Gaca M, Jones EH, Iredale JP, Arthur MJ . Progelatinase A is produced and activated by rat hepatic stellate cells and promotes their proliferation. Hepatology 1999; 30: 977–86.
Maquoi E, Frankenne F, Baramova E, Munau C, Sounni NE, Remacle A, et al. Membrane type 1 matrix metalloproteinase-associated degradation of tissue inhibitor of metalloproteinase 2 in human tumor cell lines. J Biol Chem 2000; 14: 11368–78.
Zhao H, Bernardo MM, Osenkowski P, Sohail A, Pei D, Nagase H, et al. Differential inhibition of membrane type 3 (MT3)-matrix metalloproteinase (MMP) and MT1-MMP by tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-3 rgulates pro-MMP-2 activation. J Biol Chem 2004; 279: 8592–601.
Li L, Mamputu JC, Wiernsperger N, Renier G . Signaling pathways involved in human vascular smooth muscle cell proliferation and matrix metalloproteinase-2 expression induced by leptin: inhibitory effect of metformin. Diabetes 2005; 54: 2227–34.
Chen A, Zhang L, Xu J, Tang J . The antioxidant (-)-epigallo-catechin-3-gallate inhibits activated hepatic stellate cell growth and suppresses acetaldehyde-induced gene expression. Biochem J 2002; 368: 695–704.
Johnson SJ, Hines JE, Burt AD . Macrophage and perisinusoidal cell kinetics in acute liver injury. J Pathol 1992; 166: 351–8.
Marra F, Romanelli RG, Giannini C, Failli P, Pastacaldi S, Arrighi MC, et al. Monocyte chemotactic protein-1 as a chemoattractant for human hepatic stellate cells. Hepatology 1999; 29: 140–8.
Kikuchi S, Griffin CT, Wang SS, Bissell DM . Role of CD44 in epithelial wound repair: migration of rat hepatic stellate cells utilizes hyaluronic acid and CD44v6. J Biol Chem 2005; 15: 15398–404.
Maeda K, Kuzuya M, Cheng XW, Asai T, Kanda S, Tamaya-Mori N, et al. Green tea catechins inhibit the cultured smooth muscle cell invasion through the basement barrier. Atherosclerosis 2003; 166: 23–30.
Takahara T, Fukui K, Yata Y, Jin B, Zhang LP, Nambu S, et al. Dual expression of matrix metalloproteinase-2 and membrane-type 1-matrix metalloproteinase in fibrotic human livers. Hepatology 1997; 26: 1521–9.
Olaso E, Ikeda K, Eng FJ, Xu L, Wang LH, Lin HC, et al. DDR2 receptor promotes MMP-2-mediated proliferation and invasion by hepatic stellate cells. J Clin Invest 2001; 108: 1369–78.
Rice-Evans C . Implications of the mechanisms of action of tea polyphenols as antioxidants in vitro for chemoprevention in humans. Proc Soc Exp Biol Med 1999; 220: 262–6.
Nakamuta M, Higashi N, Kohjima M, Fukushima M, Ohta S, Kotoh K, et al. Epigallocatechin-3-gallate, a polyphenol component of green tea, suppresses both collagen production and collagenase activity in hepatic stellate cells. Int J Mol Med 2005; 16: 677–81.
Higashi N, Kohjima M, Fukushima M . Epigallocatechin-3-gallate, a green-tea polyphenol, suppresses Rho signaling in TWNT-4 human hepatic stellate cells. J Lab Clin Med 2005; 145: 316–22.
Sakata R, Ueno T, Nakamura T, Sakamoto M, Torimura T, Sata M . Green tea polyphenol epigallocatechin-3-gallate inhibits platelet-derived growth factor-induced proliferation of human hepatic stellate cell line LI90. J Hepatol 2004; 40: 52–9.
Author information
Authors and Affiliations
Corresponding author
Additional information
Project supported by the Science and Technology Foundation of Guangzhou city (No 2004Z2-E0132).
Rights and permissions
About this article
Cite this article
Zhen, Mc., Huang, Xh., Wang, Q. et al. Green tea polyphenol epigallocatechin-3-gallate suppresses rat hepatic stellate cell invasion by inhibition of MMP-2 expression and its activation. Acta Pharmacol Sin 27, 1600–1607 (2006). https://doi.org/10.1111/j.1745-7254.2006.00439.x
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1111/j.1745-7254.2006.00439.x
Keywords
This article is cited by
-
Experimental models of liver fibrosis
Archives of Toxicology (2016)
-
A comprehensive overview of hepatoprotective natural compounds: mechanism of action and clinical perspectives
Archives of Toxicology (2016)
-
Tea polyphenols as an antivirulence compound Disrupt Quorum-Sensing Regulated Pathogenicity of Pseudomonas aeruginosa
Scientific Reports (2015)
-
The anti-fibrotic effects of epigallocatechin-3-gallate in bile duct-ligated cholestatic rats and human hepatic stellate LX-2 cells are mediated by the PI3K/Akt/Smad pathway
Acta Pharmacologica Sinica (2015)
-
Suppression of cancer progression and metastasis in HT-29 human colorectal adenocarcinomas by deep sea water
Biotechnology and Bioprocess Engineering (2013)