Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
권호 표지
DOI QR코드

DOI QR Code

Ginsenoside F2 attenuates chronic-binge ethanol-induced liver injury by increasing regulatory T cells and decreasing Th17 cells

  • Kim, Myung-Ho (Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology) ;
  • Kim, Hee-Hoon (Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology) ;
  • Jeong, Jong-Min (Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology) ;
  • Shim, Young-Ri (Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology) ;
  • Lee, Jun-Hee (Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology) ;
  • Kim, Ye Eun (Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology) ;
  • Ryu, Tom (Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology) ;
  • Yang, Keungmo (Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology) ;
  • Kim, Kyu-Rae (Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology) ;
  • Jeon, Byeong-Min (Department of Biological Sciences, Korea Advanced Institute of Science and Technology) ;
  • Kim, Sun Chang (Department of Biological Sciences, Korea Advanced Institute of Science and Technology) ;
  • Jung, Jae-Kwang (Department of Oral Medicine, School of Dentistry, Kyungpook National University) ;
  • Choi, Jae-Kap (Department of Oral Medicine, School of Dentistry, Kyungpook National University) ;
  • Lee, Young-Sun (Department of Internal Medicine, Korea University College of Medicine) ;
  • Byun, Jin-Seok (Department of Oral Medicine, School of Dentistry, Kyungpook National University) ;
  • Jeong, Won-Il (Laboratory of Liver Research, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology)
  • Received : 2019.09.19
  • Accepted : 2020.03.16
  • Published : 2020.11.15
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Recently, beneficial roles of ginsenoside F2 (GF2), a minor constituent of Panax ginseng, have been demonstrated in diverse inflammatory diseases. However, its roles in alcoholic liver inflammation and injury have not been clearly understood. Here, we investigated the underlying mechanism by which GF2 ameliorated alcoholic liver injury. Methods: To induce alcoholic liver injury, C57BL/6J wild type (WT) or interleukin (IL)-10 knockout (KO) mice were orally administered with ethanol (3 g/kg) or ethanol-containing GF2 (50 mg/kg) for 2 wk. Liver injury and infiltration of macrophages and neutrophils were evaluated by serum biochemistry and immunohistochemistry, respectively. The changes of hepatic immune cells were assessed by flow cytometry and polymerase chain reaction analysis. In vitro differentiation of naïve T cells was performed. Results: GF2 treatment significantly attenuated alcoholic liver injury, in which infiltrations of inflammatory macrophages and neutrophils were decreased. Moreover, the frequencies of Foxp3+ regulatory T cells (Tregs) increased but IL-17-producing T (Th17) cells decreased in GF2-treated mice compared to controls. Furthermore, the mRNA expression of IL-10 and Foxp3 was significantly increased, whereas IL-17 mRNA expression was suppressed in GF2-treated mice. However, these beneficial roles of GF2 were not observed in GF2-treated IL-10 KO mice, suggesting a critical role of IL-10. Similarly, GF2 treatment suppressed differentiation of naïve T cells into Th17 cells by inhibiting RORgt expression and stimulating Foxp3 expression. Conclusion: The present study suggests that GF2 treatment attenuates alcoholic liver injury by increasing IL-10 expression and Tregs and decreasing IL-17 expression and Th17 cells.

Keywords

References

  1. Lee SM, Bae B-S, Park H-W, Ahn N-G, Cho B-G, Cho Y-L, Kwak Y-S. Characterization of Korean red ginseng (Panax ginseng Meyer): history, preparation method, and chemical composition. J Ginseng Res 2015;39(4):384-91. https://doi.org/10.1016/j.jgr.2015.04.009
  2. Kim J-H. Pharmacological and medical applications of Panax ginseng and ginsenosides: a review for use in cardiovascular diseases. J Ginseng Res 2018;42(3):264-9. https://doi.org/10.1016/j.jgr.2017.10.004
  3. Leung KW, Wong AS-T. Pharmacology of ginsenosides: a literature review. Chinese Med 2010;5(1):20. https://doi.org/10.1186/1749-8546-5-20
  4. Huu Tung N, Uto T, Morinaga O, Kim YH, Shoyama Y. Pharmacological effects of ginseng on liver functions and diseases: a minireview. Evidence-based complementary and alternative medicine. eCAM 2012;2012:173297.
  5. Cui CH, Kim JK, Kim SC, Im WT. Characterization of a ginsenosidetransforming beta-glucosidase from Paenibacillus mucilaginosus and its application for enhanced production of minor ginsenoside F(2). PLoS One 2014;9(1):e85727. https://doi.org/10.1371/journal.pone.0085727
  6. Siraj FM, SathishKumar N, Kim YJ, Kim SY, Yang DC. Ginsenoside F2 possesses anti-obesity activity via binding with PPARgamma and inhibiting adipocyte differentiation in the 3T3-L1 cell line. J Enzyme Inhib Med Chem 2015;30(1):9-14. https://doi.org/10.3109/14756366.2013.871006
  7. Shin HS, Park SY, Hwang ES, Lee DG, Song HG, Mavlonov GT, Yi TH. The inductive effect of ginsenoside F2 on hair growth by altering the WNT signal pathway in telogen mouse skin. Eur J Pharmacol 2014;730:82-9. https://doi.org/10.1016/j.ejphar.2014.02.024
  8. Park SH, Seo W, Eun HS, Kim SY, Jo E, Kim MH, Choi WM, Lee JH, Shim YR, Cui CH, et al. Protective effects of ginsenoside F2 on 12-O-tetradecanoylphorbol-13-acetate-induced skin inflammation in mice. Biochem Biophys Res Commun 2016;478(4):1713-9. https://doi.org/10.1016/j.bbrc.2016.09.009
  9. Mai TT, Moon J, Song Y, Viet PQ, Phuc PV, Lee JM, Yi TH, Cho M, Cho SK. Ginsenoside F2 induces apoptosis accompanied by protective autophagy in breast cancer stem cells. Canc Lett 2012;321(2):144-53. https://doi.org/10.1016/j.canlet.2012.01.045
  10. Shield KD, Parry C, Rehm J. Chronic diseases and conditions related to alcohol use. Alcohol Res 2014;35(2):155-73.
  11. Louvet A, Mathurin P. Alcoholic liver disease: mechanisms of injury and targeted treatment. Nat Rev Gastroenterol Hepatol 2015;12(4):231-42. https://doi.org/10.1038/nrgastro.2015.35
  12. Albano E, Vidali M. Immune mechanisms in alcoholic liver disease. Genes Nutr 2010;5(2):141-7. https://doi.org/10.1007/s12263-009-0151-4
  13. Wang HJ, Gao B, Zakhari S, Nagy LE. Inflammation in alcoholic liver disease. Annu Rev Nutr 2012;32(1):343-68. https://doi.org/10.1146/annurev-nutr-072610-145138
  14. Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 2011;141(5):1572-85. https://doi.org/10.1053/j.gastro.2011.09.002
  15. Mandrekar P, Ambade A. Immunity and inflammatory signaling in alcoholic liver disease. Hepatol Int 2014;8(Suppl 2):439-46. https://doi.org/10.1007/s12072-014-9518-8
  16. Lee Y-S, Kim M-H, Yi H-S, Kim SY, Kim H-H, Kim JH, Yeon JE, Byun KS, Byun JS, Jeong W-I. CX3CR1 differentiates F4/80low monocytes into pro-inflammatory F4/80high macrophages in the liver. Sci Rep 2018;8(1):15076. https://doi.org/10.1038/s41598-018-33440-9
  17. Albano E. Role of adaptive immunity in alcoholic liver disease. Int J Hepatol 2012;2012:893026. https://doi.org/10.1155/2012/893026
  18. Hammerich L, Heymann F, Tacke F. Role of IL-17 and Th17 cells in liver diseases. Clin Dev Immunol 2011;2011:345803.
  19. Lee JH, Shim YR, Seo W, Kim MH, Choi WM, Kim HH, Kim YE, Yang K, Ryu T, Jeong JM, et al. Mitochondrial double-stranded RNA in exosome promotes interleukin-17 production through toll-like receptor 3 in alcoholic liver injury. Hepatology 2019.
  20. Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 2012;30:531-64. https://doi.org/10.1146/annurev.immunol.25.022106.141623
  21. Jeffery HC, Braitch MK, Brown S, Oo YH. Clinical potential of regulatory T cell therapy in liver diseases: an overview and current perspectives. Front Immunol 2016;7:334. https://doi.org/10.3389/fimmu.2016.00334
  22. Wang H, Wu T, Wang Y, Wan X, Qi J, Li L, Wang X, Luo X, Ning Q. Regulatory T cells suppress excessive lipid accumulation in alcoholic liver disease. J Lipid Res 2019;60(5):922-36. https://doi.org/10.1194/jlr.M083568
  23. Ziegler SF, Buckner JH. FOXP3 and the regulation of Treg/Th17 differentiation. Microb Infect 2009;11(5):594-8. https://doi.org/10.1016/j.micinf.2009.04.002
  24. Du R, Zhao H, Yan F, Li H. IL-17+Foxp3+ T cells: an intermediate differentiation stage between Th17 cells and regulatory T cells. J Leukoc Biol 2014;96(1):39-48. https://doi.org/10.1189/jlb.1RU0114-010RR
  25. Wang M, Zhang X-J, Liu F, Hu Y, He C, Li P, Su H, Wan J-B. Saponins isolated from the leaves of Panax notoginseng protect against alcoholic liver injury via inhibiting ethanol-induced oxidative stress and gut-derived endotoxinmediated inflammation. J Funct Foods 2015;19:214-24. https://doi.org/10.1016/j.jff.2015.09.029
  26. Li J-p, Gao Y, Chu S-f, Zhang Z, Xia C-y, Mou Z, Song X-y, He W-b, Guo X-f, Chen N-h. Nrf2 pathway activation contributes to anti-fibrosis effects of ginsenoside Rg1 in a rat model of alcohol-and CCl 4-induced hepatic fibrosis. Acta Pharmacol Sin 2014;35(8):1031. https://doi.org/10.1038/aps.2014.41
  27. Gao Y, Chu S, Li J, Li J, Zhang Z, Xia C, Heng Y, Zhang M, Hu J, Wei G, et al. Antiinflammatory function of ginsenoside Rg1 on alcoholic hepatitis through glucocorticoid receptor related nuclear factor-kappa B pathway. J Ethnopharmacol 2015;173:231-40. https://doi.org/10.1016/j.jep.2015.07.020
  28. Ni S, Li S, Yang N, Tang X, Zhang S, Hu D, Lu M. Deregulation of regulatory T cells in acute-on-chronic liver failure: a rat model. Mediators Inflamm 2017;2017:1390458.
  29. Chaudhry A, Samstein RM, Treuting P, Liang Y, Pils MC, Heinrich J-M, Jack RS, Wunderlich FT, Bruning JC, Muller W, et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 2011;34(4):566-78. https://doi.org/10.1016/j.immuni.2011.03.018
  30. Pandiyan P, Zhu J. Origin and functions of pro-inflammatory cytokine producing Foxp3+ regulatory T cells. Cytokine 2015;76(1):13-24. https://doi.org/10.1016/j.cyto.2015.07.005
  31. Kim J, Byeon H, Im K, Min H. Effects of ginsenosides on regulatory T cell differentiation. Food Sci Biotechnol 2017;27(1):227-32. https://doi.org/10.1007/s10068-017-0255-3
  32. Bae J, Koo J, Kim S, Park T-Y, Kim M-Y. Ginsenoside Rp1 exerts antiinflammatory effects via activation of dendritic cells and regulatory T cells. J Ginseng Res 2012;36(4):375-82. https://doi.org/10.5142/jgr.2012.36.4.375
  33. Zhang T, Liang Y, Zuo P, Yan M, Jing S, Li T, Wang Y, Zhang J, Wei Z. Identification of 20(R, S)-protopanaxadiol and 20(R, S)-protopanaxatriol for potential selective modulation of glucocorticoid receptor. Food Chem Toxicol 2019:110642.
  34. Hien TT, Kim ND, Pokharel YR, Oh SJ, Lee MY, Kang KW. Ginsenoside Rg3 increases nitric oxide production via increases in phosphorylation and expression of endothelial nitric oxide synthase: essential roles of estrogen receptor-dependent PI3-kinase and AMP-activated protein kinase. Toxicol Appl Pharmacol 2010;246(3):171-83. https://doi.org/10.1016/j.taap.2010.05.008
  35. Ugor E, Prenek L, Pap R, Berta G, Ernszt D, Najbauer J, Nemeth P, Boldizsar F, Berki T. Glucocorticoid hormone treatment enhances the cytokine production of regulatory T cells by upregulation of Foxp3 expression. Immunobiology 2018;223(4-5):422-31. https://doi.org/10.1016/j.imbio.2017.10.010
  36. Tai P, Wang J, Jin H, Song X, Yan J, Kang Y, Zhao L, An X, Du X, Chen X, et al. Induction of regulatory T cells by physiological level estrogen. J Cell Physiol 2008;214(2):456-64. https://doi.org/10.1002/jcp.21221

Cited by

  1. Ginsenoside F2 Suppresses Adipogenesis in 3T3-L1 Cells and Obesity in Mice via the AMPK Pathway vol.69, pp.32, 2020, https://doi.org/10.1021/acs.jafc.1c03420