Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Ginsenoside Rg3 promotes inflammation resolution through M2 macrophage polarization

  • Kang, Saeromi (Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University) ;
  • Park, Soo-Jin (Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University) ;
  • Lee, Ae-Yeon (Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University) ;
  • Huang, Jin (Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University) ;
  • Chung, Hae-Young (Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University) ;
  • Im, Dong-Soon (Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University)
  • Received : 2016.05.20
  • Accepted : 2016.12.22
  • Published : 2018.01.15
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Abstract

Background: Ginsenosides have been reported to have many health benefits, including anti-inflammatory effects, and the resolution of inflammation is now considered to be an active process driven by M2-type macrophages. In order to determine whether ginsenosides modulate macrophage phenotypes to reduce inflammation, 11 ginsenosides were studied with respect to macrophage polarization and the resolution of inflammation. Methods: Mouse peritoneal macrophages were polarized into M1 or M2 phenotypes. Reverse transcription-polymerase chain reaction, Western blotting, and measurement of nitric oxide (NO) and prostaglandin $E_2$ levels were performed in vitro and in a zymosan-induced peritonitis C57BL/6 mouse model. Results: Ginsenoside $Rg_3$ was identified as a proresolving ginseng compound based on the induction of M2 macrophage polarization. Ginsenoside $Rg_3$ not only induced the expression of arginase-1 (a representative M2 marker gene), but also suppressed M1 marker genes, such as inducible NO synthase, and NO levels. The proresolving activity of ginsenoside $Rg_3$ was also observed in vivo in a zymosan-induced peritonitis model. Ginsenoside $Rg_3$ accelerated the resolution process when administered at peak inflammatory response into the peritoneal cavity. Conclusion: These results suggest that ginsenoside $Rg_3$ induces the M2 polarization of macrophages and accelerates the resolution of inflammation. This finding opens a new avenue in ginseng pharmacology.

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References

  1. Choi KT. Botanical characteristics, pharmacological effects and medicinal components of Korean Panax ginseng C A Meyer. Acta Pharmacol Sin 2008;29: 1109-18. https://doi.org/10.1111/j.1745-7254.2008.00869.x
  2. Im DS, Nah SY. Yin and Yang of ginseng pharmacology: ginsenosides vs gintonin. Acta Pharmacol Sin 2013;34:1367-73. https://doi.org/10.1038/aps.2013.100
  3. Nah SY, Kim DH, Rhim H. Ginsenosides: are any of them candidates for drugs acting on the central nervous system? CNS Drug Rev 2007;13:381-404.
  4. Shin YM, Jung HJ, Choi WY, Lim CJ. Antioxidative, anti-inflammatory, and matrix metalloproteinase inhibitory activities of 20(S)-ginsenoside $Rg_3$ in cultured mammalian cell lines. Mol Biol Rep 2013;40:269-79. https://doi.org/10.1007/s11033-012-2058-1
  5. Jovanovski E, Bateman EA, Bhardwaj J, Fairgrieve C, Mucalo I, Jenkins AL, Vuksan V. Effect of $Rg_3$-enriched Korean red ginseng (Panax ginseng) on arterial stiffness and blood pressure in healthy individuals: a randomized controlled trial. J Am Soc Hypertens 2014;8:537-41. https://doi.org/10.1016/j.jash.2014.04.004
  6. Qiu XM, Bai X, Jiang HF, He P, Wang JH. 20-(S)-ginsenoside $Rg_3$ induces apoptotic cell death in human leukemic U937 and HL-60 cells through PI3K/ Akt pathways. Anticancer Drugs 2014;25:1072-80. https://doi.org/10.1097/CAD.0000000000000147
  7. Park D, Bae DK, Jeon JH, Lee J, Oh N, Yang G, Yang YH, Kim TK, Song J, Sun HL. Immunopotentiation and antitumor effects of a ginsenoside Rg(3)-fortified red ginseng preparation in mice bearing H460 lung cancer cells. Environ Toxicol Pharmacol 2011;31:397-405. https://doi.org/10.1016/j.etap.2011.01.008
  8. Choi SY, Cho CW, Lee Y, Kim SS, Lee SH, Kim KT. Comparison of ginsenoside and phenolic ingredient contents in hydroponically-cultivated ginseng leaves, fruits, and roots. J Ginseng Res 2012;36:425-9. https://doi.org/10.5142/jgr.2012.36.4.425
  9. Hwang JT, Lee MS, Kim HJ, Sung MJ, Kim HY, Kim MS, Kwon DY. Antiobesity effect of ginsenoside $Rg_3$ involves the AMPK and PPAR-gamma signal pathways. Phytother Res 2009;23:262-6. https://doi.org/10.1002/ptr.2606
  10. Kim HS, Lee EH, Ko SR, Choi KJ, Park JH, Im DS. Effects of ginsenosides $Rg_3$ and $Rh_2$ on the proliferation of prostate cancer cells. Arch Pharm Res 2004;27: 429-35. https://doi.org/10.1007/BF02980085
  11. Serhan CN, Krishnamoorthy S, Recchiuti A, Chiang N. Novel anti-inflammatoryepro-resolving mediators and their receptors. Curr Top Med Chem 2011;11:629-47. https://doi.org/10.2174/1568026611109060629
  12. Serhan CN, Chiang N, Dalli J. The resolution code of acute inflammation: novel pro-resolving lipid mediators in resolution. Semin Immunol 2015;27: 200-15. https://doi.org/10.1016/j.smim.2015.03.004
  13. Ramon S, Dalli J, Sanger JM, Winkler JW, Aursnes M, Tungen JE, Hansen TV, Serhan CN. The protectin PCTR1 is produced by human M2 macrophages and enhances resolution of infectious inflammation. Am J Pathol 2016;186: 962-73. https://doi.org/10.1016/j.ajpath.2015.12.012
  14. Ariel A, Serhan CN. New lives given by cell death: macrophage differentiation following their encounter with apoptotic leukocytes during the resolution of inflammation. Front Immunol 2012;3:4.
  15. Park SJ, Lee KP, Kang S, Lee J, Sato K, Chung HY, Okajima H, Im DS. Sphingosine 1-phosphate induced anti-atherogenic and atheroprotective M2 macrophage polarization through IL-4. Cell Signal 2014;26:2249-58. https://doi.org/10.1016/j.cellsig.2014.07.009
  16. Ryu YK, Lee JW, Moon EY. Thymosin beta-4, actin-sequestering protein regulates vascular endothelial growth factor expression via hypoxia-inducible nitric oxide production in HeLa cervical cancer cells. Biomol Ther (Seoul) 2015;23:19-25. https://doi.org/10.4062/biomolther.2014.101
  17. Lee JW, Kim NH, Kim JY, Park JH, Shin SY, Kwon YS, Lee HJ, Kim SS, Chun W. Aromadendrin inhibits lipopolysaccharide-induced nuclear translocation of NF-${\kappa}B$ and phosphorylation of JNK in RAW 264.7 macrophage cells. Biomol Ther 2013;21:216-21. https://doi.org/10.4062/biomolther.2013.023
  18. Sohn YA, Hwang SA, Lee SY, Hwang IY, Kim SW, Kim SY, Moon A, Lee YS, Kim YH, Kang KJ, et al. Protective effect of liriodendrin isolated from Kalopanax pictus against gastric injury. Biomol Ther (Seoul) 2015;23:53-9. https://doi.org/10.4062/biomolther.2014.103
  19. Lee HN, Kundu JK, Cha YN, Surh YJ. Resolvin D1 stimulates efferocytosis through p50/p50-mediated suppression of tumor necrosis factor-alpha expression. J Cell Sci 2013;126:4037-47. https://doi.org/10.1242/jcs.131003
  20. Yoon SJ, Park JY, Choi S, Lee JB, Jung H, Kim TD, Yoon SR, Choi I, Shim S, Park YJ. Ginsenoside $Rg_3$ regulates S-nitrosylation of the NLRP3 inflammasome via suppression of iNOS. Biochem Biophys Res Commun 2015;463:1184-9. https://doi.org/10.1016/j.bbrc.2015.06.080
  21. Keum YS, Han SS, Chun KS, Park KK, Park JH, Lee SK, Surh YJ. Inhibitory effects of the ginsenoside $Rg_3$ on phorbol ester-induced cyclooxygenase-2 expression, NFkappaB activation and tumor promotion. Mutat Res 2003;523-4:75-85.
  22. Joo SS, Yoo YM, Ahn BW, Nam SY, Kim YB, Hwang KW, Lee DI. Prevention of inflammation-mediated neurotoxicity by $Rg_3$ and its role in microglial activation. Biol Pharm Bull 2008;31:1392-6. https://doi.org/10.1248/bpb.31.1392
  23. Cheng Z, Li L. Ginsenoside $Rg_3$ ameliorates lipopolysaccharide-induced acute lung injury in mice through inactivating the nuclear factor-kappaB (NF-kappaB) signaling pathway. Int Immunopharmacol 2016;34:53-9. https://doi.org/10.1016/j.intimp.2016.02.011

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