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http://dx.doi.org/10.1016/j.jgr.2017.08.003

Enhanced Rg3 negatively regulates Th1 cell responses  

Cho, Minkyoung (Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University)
Choi, Garam (Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University)
Shim, Inbo (Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University)
Chung, Yeonseok (Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University)
Publication Information
Journal of Ginseng Research / v.43, no.1, 2019 , pp. 49-57 More about this Journal
Abstract
Background: Korean Red Ginseng (KRG; Panax ginseng Meyer) is a widely used medicinal herb known to exert various immune modulatory functions. KRG and one of its purified components, ginsenoside Rg3, are known to possess anti-inflammatory activities. How they impact helper T cell-mediated responses is not fully explored. In this study, we attempted to evaluate the effect of KRG extract (KRGE) and ginsenoside Rg3 on Th1 cell responses. Methods: Using well-characterized T cell in vitro differentiation systems, we examined the effects of KRGE or enhanced Rg3 on the Th1-inducing cytokine production from dendritic cells (DC) and the naïve $CD4^+$ T cells differentiation to Th1 cells. Furthermore, we examined the change of Th1 cell population in the intestine after treatment of enhanced Rg3. The influence of KRGE or enhanced Rg3 on Th1 cell differentiation was evaluated by fluorescence-activated cell sorting, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction. Results: KRGE significantly inhibited the production level of IL-12 from DCs and subsequent Th1 cell differentiation. Similarly, enhanced Rg3 significantly suppressed the expression of interferon gamma ($IFN{\gamma}$) and T-bet in T cells under Th1-skewing condition. Consistent with these effects in vitro, oral administration of enhanced Rg3 suppressed the frequency of Th1 cells in the Peyer's patch and lamina propria cells in vivo. Conclusion: Enhanced Rg3 negatively regulates the differentiation of Th1 cell in vitro and Th1 cell responses in the gut in vivo, providing fundamental basis for the use of this agent to treat Th1-related diseases.
Keywords
Enhanced Rg3; $IFN{\gamma}$; IL-12; Korean Red Ginseng extract; Th1;
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1 Jin SH, Park JK, Nam KY, Park SN, Jung NP. Korean red ginseng saponins with low ratios of protopanaxadiol and protopanaxatriol saponin improve scopolamine-induced learning disability and spatial working memory in mice. J Ethnopharmacol 1999;66:123-9.   DOI
2 Heo JH, Lee ST, Chu K, Oh MJ, Park HJ, Shim JY, Kim M. An open-label trial of Korean red ginseng as an adjuvant treatment for cognitive impairment in patients with Alzheimer's disease. Eur J Neurol 2008;15:865-8.   DOI
3 Kaneko H, Nakanishi K. Proof of the mysterious efficacy of ginseng: basic and clinical trials: clinical effects of medical ginseng, Korean red ginseng: specifically, its anti-stress action for prevention of disease. J Pharmacol Sci 2004;95:158-62.   DOI
4 Kim MK, Lee JW, Lee KY, Yang DC. Microbial conversion of major ginsenoside rb(1) to pharmaceutically active minor ginsenoside rd. J Microbiol 2005;43:456-62.
5 Liu WK, Xu SX, Che CT. Anti-proliferative effect of ginseng saponins on human prostate cancer cell line. Life Sci 2000;67:1297-306.   DOI
6 Lu JM, Yao Q, Chen C. Ginseng compounds: an update on their molecular mechanisms and medical applications. Curr Vasc Pharmacol 2009;7:293-302.   DOI
7 Kwon SW, Han SB, Park IH, Kim JM, Park MK, Park JH. Liquid chromatographic determination of less polar ginsenosides in processed ginseng. J Chromatogr A 2001;921:335-9.   DOI
8 Lau AJ, Seo BH, Woo SO, Koh HL. High-performance liquid chromatographic method with quantitative comparisons of whole chromatograms of raw and steamed Panax notoginseng. J Chromatogr A 2004;1057:141-9.   DOI
9 Zhang W, Zhang Y, Ma X, Chen Y. Effects of acupuncturing Pishu combined with ginsenoside Rg3 on the immune function of rats with chronic fatigue. Int J Clin Exp Med 2015;8:19022-9.
10 Yun TK. Brief introduction of Panax ginseng C.A. Meyer. J Korean Med Sci 2001;16(Suppl):S3-5.   DOI
11 Baek SH, Bae ON, Park JH. Recent methodology in ginseng analysis. J Ginseng Res 2012;36:119-34.   DOI
12 Jeon YT, Na H, Ryu H, Chung Y. Modulation of dendritic cell activation and subsequent th1 cell polarization by lidocaine. PLoS One 2015;10, e0139845.   DOI
13 Bae EA, Han MJ, Shin YW, Kim DH. Inhibitory effects of Korean red ginseng and its genuine constituents ginsenosides Rg3, Rf, and Rh2 in mouse passive cutaneous anaphylaxis reaction and contact dermatitis models. Biol Pharm Bull 2006;29:1862-7.   DOI
14 Zhou W, Zhang F, Aune TM. Either IL-2 or IL-12 is sufficient to direct Th1 differentiation by nonobese diabetic T cells. J Immunol 2003;170:735-40.   DOI
15 Manetti R, Parronchi P, Giudizi MG, Piccinni MP, Maggi E, Trinchieri G, Romagnani S. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med 1993;177:1199-204.   DOI
16 Neurath MF, Weigmann B, Finotto S, Glickman J, Nieuwenhuis E, Iijima H, Mizoguchi A, Mizoguchi E, Mudter J, Galle PR, et al. The transcription factor Tbet regulates mucosal T cell activation in experimental colitis and Crohn's disease. J Exp Med 2002;195:1129-43.   DOI
17 Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA, et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 2002;415:536-41.   DOI
18 Takei M, Tachikawa E, Umeyama A. Dendritic cells promoted by ginseng saponins drive a potent Th1 polarization. Biomark Insights 2008:3269-86.
19 Yang Y, Xu J, Niu Y, Bromberg JS, Ding Y. T-bet and eomesodermin play critical roles in directing T cell differentiation to Th1 versus Th17. J Immunol 2008;181:8700-10.   DOI
20 Park BG, Jung HJ, Cho YW, Lim HW, Lim CJ. Potentiation of antioxidative and anti-inflammatory properties of cultured wild ginseng root extract through probiotic fermentation. J Pharm Pharmacol 2013;65:457-64.   DOI
21 Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:245-52.   DOI
22 Park MW, Ha J, Chung SH. 20(S)-ginsenoside Rg3 enhances glucosestimulated insulin secretion and activates AMPK. Biol Pharm Bull 2008;31:748-51.   DOI
23 Sun HY, Lee JH, Han YS, Yoon YM, Yun CW, Kim JH, Song YS, Lee SH. Pivotal roles of ginsenoside Rg3 in tumor apoptosis through regulation of reactive oxygen species. Anticancer Res 2016;36:4647-54.   DOI
24 Banchereau J, Palucka AK. Dendritic cells as therapeutic vaccines against cancer. Nat Rev Immunol 2005;5:296-306.   DOI
25 Pooley JL, Heath WR, Shortman K. Cutting edge: intravenous soluble antigen is presented to CD4 T cells by CD8- dendritic cells, but cross-presented to CD8 T cells by CD8+ dendritic cells. J Immunol 2001;166:5327-30.   DOI
26 Takei M, Tachikawa E, Hasegawa H, Lee JJ. Dendritic cells maturation promoted by M1 and M4, end products of steroidal ginseng saponins metabolized in digestive tracts, drive a potent Th1 polarization. Biochem Pharmacol 2004;68:441-52.   DOI
27 Zhang W, Cho SY, Xiang G, Min KJ, Yu Q, Jin JO. Ginseng berry extract promotes maturation of mouse dendritic cells. PLoS One 2015;10, e0130926.   DOI
28 Kim MH, Byon YY, Ko EJ, Song JY, Yun YS, Shin T, Joo HG. Immunomodulatory activity of ginsan, a polysaccharide of panax ginseng, on dendritic cells. Korean J Physiol Pharmacol 2009;13:169-73.   DOI
29 Su W, Sun AJ, Xu DL, Zhang HQ, Yang L, Yuan LY, Jia JG, Zou YZ, Wu YL, Wang KQ, et al. Inhibiting effects of total saponins of panax ginseng on immune maturation of dendritic cells induced by oxidized-low density lipoprotein. Cell Immunol 2010;263:99-104.   DOI
30 Good SR, Thieu VT, Mathur AN, Yu Q, Stritesky GL, Yeh N, O'Malley JT, Perumal NB, Kaplan MH. Temporal induction pattern of STAT4 target genes defines potential for Th1 lineage-specific programming. J Immunol 2009;183:3839-47.   DOI
31 O'Shea JJ, Plenge R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 2012;36:542-50.   DOI
32 Santaolalla R, Fukata M, Abreu MT. Innate immunity in the small intestine. Curr Opin Gastroenterol 2011;27:125-31.   DOI
33 Chu H, Mazmanian SK. Innate immune recognition of the microbiota promotes host-microbial symbiosis. Nat Immunol 2013;14:668-75.   DOI
34 Shale M, Schiering C, Powrie F. CD4(+) T-cell subsets in intestinal inflammation. Immunol Rev 2013;252:164-82.   DOI
35 van Wijk F, Cheroutre H. Mucosal T cells in gut homeostasis and inflammation. Expert Rev Clin Immunol 2010;6:559-66.   DOI
36 Frisullo G, Nociti V, Iorio R, Patanella AK, Plantone D, Bianco A, Marti A, Cammarota G, Tonali PA, Batocchi AP. T-bet and pSTAT-1 expression in PBMC from coeliac disease patients: new markers of disease activity. Clin Exp Immunol 2009;158:106-14.   DOI
37 Yu C, Wen XD, Zhang Z, Zhang CF, Wu XH, Martin A, Du W, He TC, Wang CZ, Yuan CS. American ginseng attenuates azoxymethane/dextran sodium sulfateinduced colon carcinogenesis in mice. J Ginseng Res 2015;39:14-21.   DOI
38 Wang L, Yu X, Yang X, Li Y, Yao Y, Lui EM, Ren G. Structural and antiinflammatory characterization of a novel neutral polysaccharide from North American ginseng (Panax quinquefolius). Int J Biol Macromol 2015:7412-7.
39 Park EY, Kim HJ, Kim YK, Park SU, Choi JE, Cha JY, Jun HS. Increase in insulin secretion induced by panax ginseng berry extracts contributes to the amelioration of hyperglycemia in streptozotocininduced diabetic mice. J Ginseng Res 2012;36:153-60.   DOI
40 Vuksan V, Sung MK, Sievenpiper JL, Stavro PM, Jenkins AL, Di Buono M, Lee KS, Leiter LA, Nam KY, Arnason JT, et al. Korean red ginseng (Panax ginseng) improves glucose and insulin regulation in well-controlled, type 2 diabetes: results of a randomized, double-blind, placebo-controlled study of efficacy and safety. Nutr Metab Cardiovasc Dis 2008;18:46-56.   DOI
41 Zhang W, Xu L, Cho SY, Min KJ, Oda T, Zhang L, Yu Q, Jin JO. Ginseng berry extract attenuates dextran sodium sulfate-induced acute and chronic colitis. Nutrients 2016;8:199.   DOI
42 Stamatos NM, Carubelli I, van de Vlekkert D, Bonten EJ, Papini N, Feng C, Venerando B, d'Azzo A, Cross AS, Wang LX, et al. LPS-induced cytokine production in human dendritic cells is regulated by sialidase activity. J Leukoc Biol 2010;88:1227-39.   DOI
43 Monteleone I, Monteleone G, Del Vecchio Blanco G, Vavassori P, Cucchiara S, MacDonald TT, Pallone F. Regulation of the T helper cell type 1 transcription factor T-bet in coeliac disease mucosa. Gut 2004;53:1090-5.   DOI
44 Mannon PJ, Fuss IJ, Mayer L, Elson CO, Sandborn WJ, Present D, Dolin B, Goodman N, Groden C, Hornung RL, et al. Anti-interleukin-12 antibody for active Crohn's disease. N Eng J Med 2004;351:2069-79.   DOI
45 Surh YJ, Ferguson LR. Dietary and medicinal antimutagens and anticarcinogens: molecular mechanisms and chemopreventive potentialehighlights of a symposium. Mutat Res 2003;523-524:1-8.   DOI
46 Jeon BH, Kim CS, Kim HS, Park JB, Nam KY, Chang SJ. Effect of Korean red ginseng on blood pressure and nitric oxide production. Acta Pharmacol Sin 2000;21:1095-100.
47 Im EJ, Yayeh T, Park SJ, Kim SH, Goo YK, Hong SB, Son YM, Kim SD, Rhee MH. Antiatherosclerotic effect of Korean red ginseng extract involves regulator of g-protein signaling 5. Evid Based Complement Altern Med 2014;2014, 985174.
48 Tung NH, Quang TH, Son JH, Koo JE, Hong HJ, Koh YS, Song GY, Kim YH. Inhibitory effect of ginsenosides from steamed ginseng-leaves and flowers on the LPS-stimulated IL-12 production in bone marrow-derived dendritic cells. Arch Pharm Res 2011;34:681-5.   DOI
49 Yokozawa T, Liu ZW. The role of ginsenoside-Rd in cisplatin-induced acute renal failure. Ren Fail 2000;22:115-27.   DOI
50 Senthil K, Veena V, Mahalakshmi M, Pulla R, Yang DC, Parvatham R. Microbial conversion of major ginsenoside Rb1 to minor ginsenoside Rd by Indian fermented food bacteria. Afr J Biotechnol 2009;8:6961-6.
51 Seong MA, Woo JK, Kang JH, Jang YS, Choi S, Jang YS, Lee TH, Jung KH, Kang DK, Hurh BS, et al. Oral administration of fermented wild ginseng ameliorates DSS-induced acute colitis by inhibiting NF-kappaB signaling and protects intestinal epithelial barrier. BMB Rep 2015;48:419-25.   DOI
52 Sathyanath R, Hanumantha Rao BR, Kim HG, Cho JH, Son CG. Saponin and non-saponin fractions of red ginseng ameliorate cisplatin-induced pica in rats. Pharm Biol 2013;51:1052-60.   DOI
53 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.   DOI
54 Han B-C, Ahn H, Lee J, Jeon E, Seo S, Jang KH, Lee S-H, Kim CH, Lee G-S. Nonsaponin fractions of Korean red ginseng extracts prime activation of NLRP3 inflammasome. J Ginseng Res 2017;41:513-23.   DOI
55 Fuss IJ, Becker C, Yang ZQ, Groden C, Hornung RL, Heller F, Neurath MF, Strober W, Mannon PJ. Both IL-12p70 and IL-23 are synthesized during active Crohn's disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody. Inflamm Bowel Dis 2006;12:9-15.   DOI
56 Sandborn WJ, Feagan BG, Fedorak RN, Scherl E, Fleisher MR, Katz S, Johanns J, Blank M, Rutgeerts P, Grp UCDS. A randomized trial of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease. Gastroenterology 2008;135:1130-41.   DOI