Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Nonsaponin fraction of Korean Red Ginseng attenuates cytokine production via inhibition of TLR4 expression

  • Ahn, Huijeong (College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University) ;
  • Han, Byung-Cheol (College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University) ;
  • Kim, Jeongeun (College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University) ;
  • Kang, Seung Goo (Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University) ;
  • Kim, Pyeung-Hyeun (Department of Molecular Bioscience, School of Biomedical Science, Kangwon National University) ;
  • Jang, Kyoung Hwa (Korea Ginseng Research Institute, Korea Ginseng Corporation) ;
  • So, Seung Ho (Korea Ginseng Research Institute, Korea Ginseng Corporation) ;
  • Lee, Seung-Ho (Korea Ginseng Research Institute, Korea Ginseng Corporation) ;
  • Lee, Geun-Shik (College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University)
  • Received : 2017.10.19
  • Accepted : 2018.03.26
  • Published : 2019.04.15
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Abstract

Background: Ginsenosides of Korean Red Ginseng extracts (RGE) and its saponin components suppress secretion of inflammasome-mediating cytokines, whereas the nonsaponin fraction (NS) of RGE oppositely stimulates cytokine secretion. Although direct exposure of NS to macrophages in mice induces cytokine production, oral administration of NS has not been studied in inflammasome-related disease in animal models. Methods: Mice were fed RGE or NS for 7 days and then developed peritonitis. Peritoneal cytokines were measured, and peritoneal exudate cells (PECs) were collected to assay expression levels of a set of toll-like receptors (TLRs) and cytokines in response to NS ingestion. In addition, the role of intestinal bacteria in NS-fed mice was assessed. The effect of preexposure to NS in bone marrow-derived macrophages (BMDMs) on cytokine production was further confirmed. Results: NS ingestion attenuated secretion of peritoneal cytokines resulting from peritonitis. In addition, the isolated PECs from NS-fed mice presented lower TLR transcription levels than PECs from control diet-fed mice. BMDMs treated with NS showed downregulation of TLR4 mRNA and protein expression, which was mediated by the $TLR4-MyD88-NF{\kappa}B$ signal pathway. BMDMs pretreated with NS produced less cytokines in response to TLR4 ligands. Conclusion: NS administration directly inhibits TLR4 expression in inflammatory cells such as macrophages, thereby reducing secretion of cytokines during peritonitis.

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References

  1. Ru W, Wang D, Xu Y, He X, Sun YE, Qian L, Zhou X, Qin Y. Chemical constituents and bioactivities of Panax ginseng (C. A. Mey.). Drug Discov Ther 2015;9: 23-32. https://doi.org/10.5582/ddt.2015.01004
  2. Baek SH, Bae ON, Park JH. Recent methodology in ginseng analysis. J Ginseng Res 2012;36:119-34. https://doi.org/10.5142/jgr.2012.36.2.119
  3. Sohn EH, Jang SA, Lee CH, Jang KH, Kang SC, Park HJ, Pyo S. Effects of Korean red ginseng extract for the treatment of atopic dermatitis-like skin lesions in mice. J Ginseng Res 2011;35:479-86. https://doi.org/10.5142/jgr.2011.35.4.479
  4. Kim J, Ahn H, Han BC, Lee SH, Cho YW, Kim CH, Hong EJ, An BS, Jeung EB, Lee GS. Korean red ginseng extracts inhibit NLRP3 and AIM2 inflammasome activation. Immunol Lett 2014;158:143-50. https://doi.org/10.1016/j.imlet.2013.12.017
  5. Kee JY, Jeon YD, Kim DS, Han YH, Park J, Youn DH, Kim SJ, Ahn KS, Um JY, Hong SH. Korean red ginseng improves atopic dermatitis-like skin lesions by suppressing expression of proinflammatory cytokines and chemokines in vivo and in vitro. J Ginseng Res 2017;41:134-43. https://doi.org/10.1016/j.jgr.2016.02.003
  6. Lim DS, Bae KG, Jung IS, Kim CH, Yun YS, Song JY. Anti-septicaemic effect of polysaccharide from Panax ginseng by macrophage activation. J Infect 2002;45:32-8. https://doi.org/10.1053/jinf.2002.1007
  7. Shin JY, Song JY, Yun YS, Yang HO, Rhee DK, Pyo S. Immunostimulating effects of acidic polysaccharides extract of Panax ginseng on macrophage function. Immunopharmacol Immunotoxicol 2002;24:469-82. https://doi.org/10.1081/IPH-120014730
  8. Choi HS, Kim KH, Sohn E, Park JD, Kim BO, Moon EY, Rhee DK, Pyo S. Red ginseng acidic polysaccharide (RGAP) in combination with IFN-gamma results in enhanced macrophage function through activation of the NF-kappaB pathway. Biosci Biotechnol Biochem 2008;72:1817-25. https://doi.org/10.1271/bbb.80085
  9. Byeon SE, Lee J, Kim JH, Yang WS, Kwak YS, Kim SY, Choung ES, Rhee MH, Cho JY. Molecular mechanism of macrophage activation by red ginseng acidic polysaccharide from Korean red ginseng. Mediat Inflamm 2012;2012. 732860.
  10. Han BC, Ahn H, Lee J, Jeon E, Seo S, Jang K, Lee SH, Kim CH, Lee GS. Nonsaponin fractions of Korean red ginseng extracts prime activation of NLRP3 inflammasome. J Ginseng Res 2017;41:513-23. https://doi.org/10.1016/j.jgr.2016.10.001
  11. Liu X, Zhang Z, Ruan J, Pan Y, Magupalli VG, Wu H, Lieberman J. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 2016;535:153-8. https://doi.org/10.1038/nature18629
  12. Lee GS. Inflammasomes, multi-cellular protein complex in myeloid cells, induce several metabolic diseases via interleukin-$1{\beta}$ maturation. J Biomed Res 2013;14:195-200. https://doi.org/10.12729/jbr.2013.14.4.195
  13. Larina L, Cho BG, Ten L, Park H. Isolation of saponin-free fraction from Ginseng (Panax ginseng C.A. Meyer) and its effects on the function of neutrophils. Korean J Chem Eng 2001;18:986-91. https://doi.org/10.1007/BF02705630
  14. Ahn H, Lee GS. Isorhamnetin and hyperoside derived from water dropwort inhibits inflammasome activation. Phytomed Int J Phytother Phytopharmacol 2017;24:77-86.
  15. Ahn H, Kang SG, Yoon SI, Kim PH, Kim D, Lee GS. Poly-gamma-glutamic acid from Bacillus subtilis upregulates pro-inflammatory cytokines while inhibiting NLRP3, NLRC4 and AIM2 inflammasome activation. Cell Mol Immunol 2016.
  16. Ahn H, Jeon E, Kim JC, Kang SG, Yoon SI, Ko HJ, Kim PH, Lee GS. Lentinan from shiitake selectively attenuates AIM2 and non-canonical inflammasome activation while inducing pro-inflammatory cytokine production. Sci Reports 2017;7:1314. https://doi.org/10.1038/s41598-017-01462-4
  17. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006;440:237-41. https://doi.org/10.1038/nature04516
  18. Lee J, Ahn H, Hong EJ, An BS, Jeung EB, Lee GS. Sulforaphane attenuates activation of NLRP3 and NLRC4 inflammasomes but not AIM2 inflammasome. Cell Immunol 2016;306-307:53-60. https://doi.org/10.1016/j.cellimm.2016.07.007
  19. Kayagaki N, Wong MT, Stowe IB, Ramani SR, Gonzalez LC, Akashi-Takamura S, Miyake K, Zhang J, Lee WP, Muszynski A, et al. Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 2013;341:1246-9. https://doi.org/10.1126/science.1240248
  20. Lu YC, Yeh WC, Ohashi PS. LPS/TLR4 signal transduction pathway. Cytokine 2008;42:145-51. https://doi.org/10.1016/j.cyto.2008.01.006
  21. Li H, Willingham SB, Ting JP, Re F. Cutting edge: inflammasome activation by alum and alum's adjuvant effect are mediated by NLRP3. J Immunol 2008;181: 17-21. https://doi.org/10.4049/jimmunol.181.1.17
  22. van de Veerdonk FL, Netea MG, Dinarello CA, Joosten LA. Inflammasome activation and IL-1beta and IL-18 processing during infection. Trends Immunol 2011;32:110-6. https://doi.org/10.1016/j.it.2011.01.003
  23. Liu-Bryan R, Scott P, Sydlaske A, Rose DM, Terkeltaub R. Innate immunity conferred by Toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation. Arthr Rheumat 2005;52:2936-46. https://doi.org/10.1002/art.21238
  24. Yang XD, Yang YY, Ouyang DS, Yang GP. A review of biotransformation and pharmacology of ginsenoside compound K. Fitoterapia 2015;100: 208-20. https://doi.org/10.1016/j.fitote.2014.11.019
  25. Lee SM, Bae BS, Park HW, Ahn NG, Cho BG, Cho YL, Kwak YS. Characterization of Korean red ginseng (Panax ginseng Meyer): history, preparation method, and chemical composition. J Ginseng Res 2015;39:384-91. https://doi.org/10.1016/j.jgr.2015.04.009
  26. Nakaya TA, Kita M, Kuriyama H, Iwakura Y, Imanishi J. Panax ginseng induces production of proinflammatory cytokines via toll-like receptor. J Interferon Cytokine Res 2004;24:93-100. https://doi.org/10.1089/107999004322813336
  27. Han BC, Ahn H, Lee J, Jeon E, Seo S, Jang KH, Lee SH, Kim CH, Lee GS. Nonsaponin fractions of Korean red ginseng extracts prime activation of NLRP3 inflammasome. J Ginseng Res 2017;41:513-23. https://doi.org/10.1016/j.jgr.2016.10.001
  28. Bang CS, Hong SH, Suk KT, Kim JB, Han SH, Sung H, Kim EJ, Kim MJ, Kim MY, Baik SK, et al. Effects of Korean red ginseng (Panax ginseng), urushiol (Rhus vernicifera Stokes), and probiotics (Lactobacillus rhamnosus R0011 and Lactobacillus acidophilus R0052) on the gut-liver axis of alcoholic liver disease. J Ginseng Res 2014;38:167-72. https://doi.org/10.1016/j.jgr.2014.04.002
  29. Nguyen CT, Rhee DK. Panax ginseng as a potential modulator of macrophages. Macrophage 2016;3:1.
  30. Zhao BS, Liu Y, Gao XY, Zhai HQ, Guo JY, Wang XY. Effects of ginsenoside Rg1 on the expression of toll-like receptor 3, 4 and their signalling transduction factors in the NG108-15 murine neuroglial cell line. Molecules 2014;19: 16925-36. https://doi.org/10.3390/molecules191016925
  31. Ahn JY, Choi IS, Shim JY, Yun EK, Yun YS, Jeong G, Song JY. The immunomodulator ginsan induces resistance to experimental sepsis by inhibiting Toll-like receptor-mediated inflammatory signals. Eur J Immunol 2006;36: 37-45. https://doi.org/10.1002/eji.200535138
  32. Pannacci M, Lucini V, Colleoni F, Martucci C, Grosso S, Sacerdote P, Scaglione F. Panax ginseng C.A. Mayer G115 modulates pro-inflammatory cytokine production in mice throughout the increase of macrophage toll-like receptor 4 expression during physical stress. Brain Behav Immun 2006;20:546-51. https://doi.org/10.1016/j.bbi.2005.11.007

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