No Access

Epigallocatechin-3-gallate Prevents Triptolide-Induced Hepatic Injury by Restoring the Th17/T_reg Balance in Mice

School of Chemistry and Chemical Engineering, Chongqing University, Shapingba District, Shazheng Avenue, No. 174, Chongqing 400044, P.R. China

These authors contributed equally to this work.

Search for more papers by this author

Rong Jiang

College of Basic Medical, Chongqing Medical University, Yuzhong District, Yixueyuan Avenue, No. 1, Chongqing 400016, P.R. China

These authors contributed equally to this work.

Search for more papers by this author

Ying Z. Mazzu

Department of Surgery, Memorial Sloan-Kettering Cancer Center, York Avenue, 1275, New York, NY 10065, USA

These authors contributed equally to this work.

Search for more papers by this author

Cai-Bing Wei

College of Basic Medical, Chongqing Medical University, Yuzhong District, Yixueyuan Avenue, No. 1, Chongqing 400016, P.R. China

Search for more papers by this author

Zong-Liang Sun

School of Chemistry and Chemical Engineering, Chongqing University, Shapingba District, Shazheng Avenue, No. 174, Chongqing 400044, P.R. China

Search for more papers by this author

Yu-Zhen Zhang

School of Chemistry and Chemical Engineering, Chongqing University, Shapingba District, Shazheng Avenue, No. 174, Chongqing 400044, P.R. China

Search for more papers by this author

Lian-Di Zhou

College of Basic Medical, Chongqing Medical University, Yuzhong District, Yixueyuan Avenue, No. 1, Chongqing 400016, P.R. China

E-mail Address: [email protected]

Correspondence to: Lian-Di Zhou, College of Basic Medical, Chongqing Medical University, Yuzhong District, Yixueyuan Avenue, No. 1, Chongqing 400016, P.R. China. Tel: (+86) 23-68485540, Fax: (+86) 23-68485785.

Search for more papers by this author

, and

Qi-Hui Zhang

School of Chemistry and Chemical Engineering, Chongqing University, Shapingba District, Shazheng Avenue, No. 174, Chongqing 400044, P.R. China

E-mail Address: [email protected]

Correspondence to: Dr. Qi-Hui Zhang, School of Chemistry and Chemical Engineering, Chongqing University, Shapingba District, Shazheng Avenue, No. 174, Chongqing 400044, P.R. China. Tel: (+86) 23-2398-6483.

Search for more papers by this author

https://doi.org/10.1142/S0192415X16500683Cited by:18 (Source: Crossref)

Abstract

Drug-induced liver injury (DILI) is the most common cause of acute liver failure. Disruption of the Th17/Treg balance can lead to hepatic inflammation, which causes the main symptoms of DILI. Here we investigate the protective mechanisms of (-)-Epigallocatechin-3-gallate (EGCG) on triptolide (TP)-induced DILI that shows the Th17/T_reg imbalance. Pretreatment with EGCG (5mg/kg) for 10 days before TP (0.5mg/kg) administration in mice significantly reduced the increased alanine aminotransferase (ALT) level ( $P < 0.05$ ) induced by TP treatment. The hepatic histology analysis further proved that EGCG protected mice from TP-induced liver injury. The imbalance of Th17/T_reg was induced by TP treatment, as shown by the upregulation of TLR4 and downregulation of Tim3 expression. EGCG pretreatment can maintain the expression of TLR4 and Tim3 at normal levels to restore the Th17/T_reg imbalance. In addition, EGCG can block the TP-induced expression of the downstream targets of TLR4, including MyD88, NF $k$ B, and retinoid related orphan receptor (ROR- $γ$ t), while EGCG can restore the TP inhibition of forkhead/winged-helix family transcriptional repressor p3 (FoxP3) that is the downstream target of Tim3. Consequently, EGCG pretreatment can effectively inhibit the Th17-related pro-inflammatory cytokine (e.g. IL-17 and IL-6) upregulation induced by TP treatment. However, TP inhibition of T_reg-related anti-inflammatory cytokine IL-10 production was restored by EGCG pretreatment. Taken together, these results suggest that EGCG possesses significant protective properties against TP-induced hepatic inflammatory injury, and that these properties are carried out via the restoration of the Th17/T_reg imbalance by the inhibition of the TLR4 signaling pathway and the enhanced activation of the Tim3 signaling pathway.

Keywords:

References

Aktas, O., T. Prozorovski, A. Smorodchenko, N.E. Savaskan, R. Lauster, P.M. Kloetzel, C. Infante-Duarte, S. Brocke and F. Zipp. Green tea epigallocatechin-3-gallate mediates T cellular NF- $κ$ B inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J. Immunol. 173: 5794–5800, 2004. Crossref, Medline, Web of Science, Google Scholar
Bao, S., Y. Cao, C. Fan, Y. Fan, S. Bai, W. Teng and Z. Shan. Epigallocatechin gallate improves insulin signaling by decreasing toll-like receptor 4 (TLR4) activity in adipose tissues of high-fat diet rats. Mol. Nutr. Food Res. 58: 677–686, 2014. Crossref, Medline, Web of Science, Google Scholar
Cabrera, C., R. Artacho and R. Giménez. Beneficial effects of green tea — a review. J. Am. Coll. Nutr. 25: 79–99, 2006. Crossref, Medline, Web of Science, Google Scholar
Chen, B.J., Triptolide, a novel immunosuppressive and anti-inflammatory agent purified from a Chinese herb Tripterygium wilfordii Hook F. Leuk Lymphoma 42: 253–265, 2001. Crossref, Medline, Web of Science, Google Scholar
Choi, B.B., J.H. Choi, S.R. Park, J.Y. Kim, J.W. Hong and G.C. Kim. Scutellariae radix induces apoptosis in chemoresistant SCC-25 human tongue squamous carcinoma cells. Am. J. Chin. Med. 43: 167–181, 2015. Link, Web of Science, Google Scholar
Duan, M.C., W. Han, P.W. Jin, Y.P. Wei, Q. Wei, L.M. Zhang and J.C. Li. Disturbed Th17/T_reg balance in patients with non-small cell lung cancer. Inflammation 38: 2156–2165, 2015. Crossref, Medline, Web of Science, Google Scholar
Fu, Q., X. Huang, B. Shu, M. Xue, P. Zhang, T. Wang, L. Liu, Z. Jiang and L. Zhang. Inhibition of mitochondrial respiratory chain is involved in triptolide-induced liver injury. Fitoterapia 82: 1241–1248, 2011. Crossref, Medline, Web of Science, Google Scholar
Galani Tietcheu, B.R., G. Sass, N.F. Njayou, P. Mkounga, G. Tiegs and P.F. Moundipa. Anti-hepatitis C virus activity of crude extract and fractions of Entada africana in genotype 1b replicon systems. Am. J. Chin. Med. 42: 853–868, 2014. Link, Web of Science, Google Scholar
Han, Y., H.W. Jung and Y.K. Park. Selective therapeutic effect of cornus officinalis fruits on the damage of different organs in STZ-induced diabetic rats. Am. J. Chin. Med. 42: 1169–1182, 2014. Link, Web of Science, Google Scholar
Hastings, W.D., D.E. Anderson, N. Kassam, K. Koguchi, E.A. Greenfield, S.C. Kent, X.X. Zheng, T.B. Strom, D.A. Hafler and V.K. Kuchroo. TIM-3 is expressed on activated human CD4 $^{+}$ T cells and regulates Th1 and Th17 cytokines. Eur. J. Immunol. 39: 2492–2501, 2009. Crossref, Medline, Web of Science, Google Scholar
Hong Byun, E., Y. Fujimura, K. Yamada and H. Tachibana. TLR4 signaling inhibitory pathway induced by green tea polyphenol epigallocatechin-3-gallate through 67-kDa laminin receptor. J. Immunol. 185: 33–45, 2010. Crossref, Medline, Web of Science, Google Scholar
Huang, S.S., J.S. Deng, J.G. Lin, C.Y. Lee and G.J. Huang. Anti-inflammatory effects of trilinolein from Panax notoginseng through the suppression of NF- $κ$ B and MAPK expression and proinflammatory cytokine expression. Am. J. Chin. Med. 42: 1485–1506, 2014. Link, Web of Science, Google Scholar
Jin, B., T. Sun, X.H. Yu, Y.X. Yang and A.E. Yeo. The effects of TLR activation on T-cell development and differentiation. Clin. Dev. Immunol. 2012: 836485, 2012. Crossref, Medline, Google Scholar
Kang, G.D., S. Lim and D.H. Kim. Oleanolic acid ameliorates dextran sodium sulfate-induced colitis in mice by restoring the balance of Th17/T_reg cells and inhibiting NF- $κ$ B signaling pathway. Int. Immunopharmacol. 29: 393–400, 2015. Crossref, Medline, Web of Science, Google Scholar
Kaplowitz, N., Drug-induced liver disorders implications for drug development and regulation. Drug Saf. 24: 483–490, 2001. Crossref, Medline, Web of Science, Google Scholar
Lao, W., Y. Tan, X. Jin, L. Xiao, J.J. Kim and X. Qu. Comparison of cytotoxicity and the anti-adipogenic effect of green tea polyphenols with epigallocatechin-3-gallate in 3T3-L1 preadipocytes. Am. J. Chin. Med. 43: 1177–1190, 2015. Link, Web of Science, Google Scholar
Leise, M.D., J.J. Poterucha and J.A. Talwalkar. Drug-induced liver injury. Mayo Clin. Proc. 89: 95–106, 2014. Crossref, Medline, Web of Science, Google Scholar
Li, J., F.P. Wang, W.M. She, C.Q. Yang, L. Li, C.T. Tu, J.Y. Wang and W. Jiang. Enhanced high-mobility group box 1 (HMGB1) modulates regulatory T cells (T_reg)/T helper 17 (Th17) balance via toll-like receptor (TLR)-4-interleukin (IL)-6 pathway in patients with chronic hepatitis B. J. Viral. Hepat. 21: 129–140, 2014. Crossref, Medline, Web of Science, Google Scholar
Liu, D., X. Zhang, L. Jiang, Y. Guo and C. Zheng. Epigallocatechin-3-gallate (EGCG) attenuates concanavalin A-induced hepatic injury in mice. Acta Histochem. 116: 654–662, 2014. Crossref, Medline, Web of Science, Google Scholar
Liu, Q., Triptolide and its expanding multiple pharmacological functions. Int. Immunopharmacol. 11: 377–383, 2011. Crossref, Medline, Web of Science, Google Scholar
Lu, Y., X. Bao, T. Sun, J. Xu, W. Zheng and P. Shen. Triptolide attenuate the oxidative stress induced by LPS/D-GalN in mice. J. Cell Biochem. 113: 1022–1033, 2012. Crossref, Medline, Web of Science, Google Scholar
Jin, H., L. Wang, C. Xu, B. Li, Q. Luo, J. Wu, Y. Lv, G. Wang and J. Dong. Effects of Psoraleae fructus and its major component psoralen on Th2 response in allergic asthma. Am. J. Chin. Med. 42: 665–678, 2014. Link, Web of Science, Google Scholar
Min, S.Y., M. Yan, S.B. Kim, S. Ravikumar, S.R. Kwon, K. Vanarsa, H.Y. Kim, L.S. Davis and C. Mohan. Green tea epigallocatechin-3-gallate suppresses autoimmune arthritis through indoleamine-2, 3-dioxygenase expressing dendritic cells and the nuclear factor, erythroid 2-like 2 antioxidant pathway. J. Inflamm. (Lond.) 12: 53, 2015. Crossref, Medline, Web of Science, Google Scholar
Mohankumar, N., P. Ranjan and A. Kumari. Drug-induced liver injury: Diagnosing (and treating) it early. J. Fam. Pract. 64: 634–644, 2015. Medline, Web of Science, Google Scholar
Morii, K., M. Nishisaka, S. Nakamura, T. Oda, Y. Aoyama, T. Yamamoto, H. Kishida, H. Okushin and K. Uesaka. A case of synthetic oestrogen-induced autoimmune hepatitis with microvesicular steatosis. J. Clin. Pharm. Ther. 39: 573–576, 2014. Crossref, Medline, Web of Science, Google Scholar
Ni, L., X. Zhu, C. Gong, Y. Luo, L. Wang, W. Zhou, S. Zhu and Y. Li. Trichosanthes kirilowii fruits inhibit non-small cell lung cancer cell growth through mitotic cell-cycle arrest. Am. J. Chin. Med. 43: 349–364, 2015. Link, Web of Science, Google Scholar
Niwa, H., T. Satoh, Y. Matsushima, K. Hosoya, K. Saeki, T. Niki, M. Hirashima and H. Yokozeki. Stable form of galectin-9, a Tim-3 ligand, inhibits contact hypersensitivity and psoriatic reactions: A potent therapeutic tool for Th1- and/or Th17-mediated skin inflammation. Clin. Immunol. 132: 184–194, 2009. Crossref, Medline, Web of Science, Google Scholar
Pandey, K.B. and S.I. Rizvi. Plant polyphenols as dietary antioxidants in human health and disease. Oxid. Med. Cell Longev. 2: 270–278, 2009. Crossref, Medline, Web of Science, Google Scholar
Sai, K., W.Y. Li, Y.S. Chen, J. Wang, S. Guan, Q.Y. Yang, C.C. Guo, Y.G. Mou, W.P. Li and Z.P. Chen. Triptolide synergistically enhances temozolomide-induced apoptosis and potentiates inhibition of NF- $κ$ B signaling in glioma initiating cells. Am. J. Chin. Med. 42: 485–503, 2014. Link, Web of Science, Google Scholar
Sanchez-Fueyo, A., J. Tian, D. Picarella, C. Domenig, X.X. Zheng, C.A. Sabatos, N. Manlongat, O. Bender, T. Kamradt, V.K. Kuchroo, J.C. Gutiérrez-Ramos, A.J. Coyle and T.B. Strom. Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nat. Immunol. 4: 1093–1101, 2003. Crossref, Medline, Web of Science, Google Scholar
Si, Y., S. Guo, Y. Fang, S. Qin, F. Li, Y. Zhang, P. Jiao, C. Zhang and L. Gao. Celery seed extract blocks peroxide injury in macrophages via notch1/NF- $κ$ B pathway. Am. J. Chin. Med. 43: 443–455, 2015. Link, Web of Science, Google Scholar
Singh, R., N. Akhtar and T.M. Haqqi. Green tea polyphenol epigallocatechin-3-gallate: Inflammation and arthritis. Life Sci. 86: 907–918, 2010. Crossref, Medline, Web of Science, Google Scholar
Song, J., M.J. Duncan, G.J. Li, C. Chan, R. Grady, A. Stapleton and S.N. Abraham. A novel TLR4-mediated signaling pathway leading to IL-6 responses in human bladder epithelial cells. PLoS Pathog. 3: e60, 2007. Crossref, Medline, Web of Science, Google Scholar
Sun, Q., Q. Liu, Y. Zheng and X. Cao. Rapamycin suppresses TLR4-triggered IL-6 and PGE2 production of colon cancer cells by inhibiting TLR4 expression and NF- $κ$ B activation. Mol. Immunol. 45: 2929–2936, 2008. Crossref, Medline, Web of Science, Google Scholar
Talaat, R.M., S.F. Mohamed, I.H. Bassyouni and A.A. Raouf. Th1/Th2/Th17/T_reg cytokine imbalance in systemic lupus erythematosus (SLE) patients: Correlation with disease activity. Cytokine 72: 146–153, 2015. Crossref, Medline, Web of Science, Google Scholar
Thichanpiang, P. and K. Wongprasert. Green tea polyphenol epigallocatechin-3-gallate attenuates TNF- $α$ -induced intercellular adhesion molecule-1 expression and monocyte adhesion to retinal pigment epithelial cells. Am. J. Chin. Med. 43: 103–119, 2015. Link, Web of Science, Google Scholar
Tipoe, G.L., T.M. Leung, E.C. Liong, T.Y. Lau, M.L. Fung and A.A. Nanji. Epigallocatechin-3-gallate (EGCG) reduces liver inflammation, oxidative stress and fibrosis in carbon tetrachloride (CCl₄)-induced liver injury in mice. Toxicology 273: 45–52, 2010. Crossref, Medline, Web of Science, Google Scholar
Tipoe, G.L., T.M. Leung, M.W. Hung and M.L. Fung. Green tea polyphenols as an antioxidant and anti-inflammatory agent for cardiovascular protection. Cardiovasc. Hematol. Disord. Drug Targets 7: 135–144, 2007. Crossref, Medline, Google Scholar
Tong, L., S.M. Nanjundaiah, S.H. Venkatesha, B. Astry, H. Yu and K.D. Moudgil. Pristimerin, a naturally occurring triterpenoid, protects against autoimmune arthritis by modulating the cellular and soluble immune mediators of inflammation and tissue damage. Clin. Immunol. 155: 220–230, 2014. Crossref, Medline, Web of Science, Google Scholar
Vignali, D.A.A., L.W. Collison and C. Workman. How regulatory T cells work. J. Nat. Rev. Immunol. 8: 523–532, 2008. Crossref, Medline, Web of Science, Google Scholar
Wang, J., Z. Jiang, J. Ji, X. Wang, T. Wang, Y. Zhang, T. Tai, M. Chen, L. Sun, X. Li and L. Zhang. Gene expression profiling and pathway analysis of hepatotoxicity induced by triptolide in Wistar rats. Food Chem. Toxicol. 58: 495–505, 2013. Crossref, Medline, Web of Science, Google Scholar
Wang, C.Y., X.Y. Bai and C.H. Wang. Traditional Chinese medicine: A treasured natural resource of anticancer drug research and development. Am. J. Chin. Med. 42: 543–559, 2014a. Link, Web of Science, Google Scholar
Wang, J., Z. Ren, Y. Xu, S. Xiao, S.N. Meydani and D. Wu. Epigallocatechin-3-gallate ameliorates experimental autoimmune encephalomyelitis by altering balance among CD4 $^{+}$ T-cell subsets. Am. J. Pathol. 180: 221–234, 2012. Crossref, Medline, Web of Science, Google Scholar
Wang, S., R. Chen, Z. Zhong, Z. Shi, M. Chen and Y. Wang. Epigallocatechin-3-gallate potentiates the effect of curcumin in inducing growth inhibition and apoptosis of resistant breast cancer cells. Am. J. Chin. Med. 42: 1279–1300, 2014b. Link, Web of Science, Google Scholar
Wang, X., Z. Jiang, W. Cao, Z. Yuan, L. Sun and L. Zhang. Th17/T_reg imbalance in triptolide-induced liver injury. Fitoterapia. 93: 245–251, 2014c. Crossref, Medline, Web of Science, Google Scholar
Wang, X.Z., Z.Z. Jiang, M.T. Xing, J. Fu, Y.W. Su, L.X. Sun and L.Y. Zhang. Interleukin-17 mediates triptolide-induced liver injury in mice. Food Chem. Toxicol. 71: 33–41, 2014d. Crossref, Medline, Web of Science, Google Scholar
Wei, Y., B. Liu, J. Sun, Y. Lv, Q. Luo, F. Liu and J. Dong. Regulation of Th17/T_reg function contributes to the attenuation of chronic airway inflammation by icariin in ovalbumin-induced murine asthma model. Immunobiology 220: 789–797, 2015. Crossref, Medline, Web of Science, Google Scholar
Wu, C., P. Wang, J. Rao, Z. Wang, C. Zhang, L. Lu and F. Zhang. Triptolide alleviates hepatic ischemia/reperfusion injury by attenuating oxidative stress and inhibiting NF- $κ$ B activity in mice. J. Surg. Res. 166: e205–e213, 2011. Crossref, Medline, Web of Science, Google Scholar
Wu, D., J. Wang, M. Pae and S.N. Meydani. Green tea EGCG, T cells, and T cell-mediated autoimmune diseases. Mol. Aspects Med. 33: 107–118, 2012. Crossref, Medline, Web of Science, Google Scholar
Yang, E.J., J. Lee, S.Y. Lee, E.K. Kim, Y.M. Moon, Y.O. Jung, S.H. Park and M.L. Cho. EGCG attenuates autoimmune arthritis by inhibition of STAT3 and HIF-1 $α$ with Th17/T_reg control. PLoS One 9, e86062, 2014. Crossref, Medline, Web of Science, Google Scholar
Zimmerman, H.J., Hepatotoxicity: The Adverse Effects of Drugs and Other Chemicals on the Liver, Lippincott Williams & Wilkins, Philadelphia, 1999, pp. 427–456. Google Scholar
Zhu, C., A.C. Anderson, A. Schubart, H. Xiong, J. Imitola, S.J. Khoury, X.X. Zheng, T.B. Strom and V.K. Kuchroo. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat. Immunol. 6: 1245–1252, 2005. Crossref, Medline, Web of Science, Google Scholar