DOI QR코드

DOI QR Code

Effects of 20(S)-Protopanaxadiol and 20(S)-Protopanaxatriol on the Inflammatory Mediators Release from the Activated Mast Cells

20(S)-Protopanaxadiol 및 20(S)-Protopanaxatriol이 활성화된 비만세포로부터의 염증 매개체 유리에 미치는 영향

  • Ro, Jai-Youl (Department of Pharmacology, School of Medicine, Sungkyunkwan University) ;
  • Han, Yong-Nam (School of Pharmacy, Seoul National University) ;
  • Choi, Kwang-Tae (The Korean Society of Ginseng) ;
  • Lee, Chang-Ho (Department of Pharmacology, College of Medicine, Hanyang University)
  • 노재열 (성균관대학교 의과대학 약리학 교실) ;
  • 한용남 (서울대학교 약학대학) ;
  • 최광태 (고려인삼학회) ;
  • 이창호 (한양대학교 의과대학 약리학 교실)
  • Published : 2009.12.31

Abstract

Ginseng saponins have various pharmacological effects on the immune system. 20(S)-protopanaxadiol (PPD) and 20(S)-protopanaxatriol (PPT) are the species of ginseng saponin metabolites that are formed by human intestinal bacteria and detected in circulation. The effects of PPD and PPT on the inflammatory mediator release from the activated mast cells were tested. Histamine release was evaluated in activated guinea pig lung mast cells, and the secretion of interleukin-4 (IL-4), interleukin-8 (IL-8), and the tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) was assessed in an HMC-1 cell after treating it with ginseng saponin metabolites. The results are as follows. PPT, at its maximum concentration of $100\;{\mu}M$, completely abolished the secretion of IL-4 from the PMA-stimulated HMC-1 cell. It also inhibited IL-8 secretion from the same cells by about 40-50% of the PMA-treated DMSO control. PPD, at its maximum concentration of $100\;{\mu}M$, showed a tendency to induce histamine release from the guinea pig lung mast cells. It inhibited the secretion of IL-4 (by 89% of the PMA-treated DMSO control) in the PMA-stimulated HMC-1 cell, but did have a significant effect on the IL-8 release from the same cell. Both PPD and PPT showed no effects, however, on the release of TNF-${\alpha}$ from the PMA-stimulated HMC-1 cell. These results suggest that PPD and PPT are from the ginseng metabolites that are responsible for the immunomodulating activity of ginseng extracts when they are taken orally.

인삼 사포닌은 면역계에 다양한 약리 효과를 발휘한다. 20(S)-프로토파낙사다이올 (PPD) 및 20(S)- 프로토파낙사트리올 (PPT)은 장내 세균에 의하여 생성되는 인삼 대사체의 일종이며 생체 내 투여 시 순환계에서 탐지된다. 활성화된 비만 세포로부터의 염증 매개체 유리에 미치는 20(S)-프로토파낙사다이올 (PPD) 및 20(S)-프로토파낙사트리올 (PPT)의 영향을 평가하였다. 인삼 사포닌 대사체를 처치 후, 히스타민 유리는 활성화된 해명 폐 비만세포에서 평가하였으며, 인터루킨-4, 인터루킨-8, 및 종양괴사인자-알파 유리는 HMC-1 비만세포에서 평가하였다. 결과는 다음과 같다. PPT는 최고 $100\;{\mu}M$ 농도에서 PMA에 의하여 자극된 HMC-1 세포로부터의 인터루킨-4 유리를 완전히 차단하였다. 또한, 이는 HMC-1 세포로부터의 인터루킨-8의 유리를, PMA와 DMSO동시 처치 시얻어진 수치를 기준으로 대략 40-50% 정도 억제하였다. PPD는 최고 $100\;{\mu}M$ 농도에서 해명 폐 비만세포로부터의 히스타민 유리를 초래하였으나 통계적 유의성은 없었다. PPD는 HMC-1 세포에 PMA와 DMSO 동시 처치 시 얻어진 수치를 기준으로 할 때, 인터루킨-4의 유리를 대략 89% 정도 억제하였으나, 인터루킨-8의 유리에는 유의적인 효과를 초래하지 않았다. 그러나 PPD 및 PPT 모두, PMA에 의하여 자극된 HMC-1 세포로부터의 종양괴사 인자-알파의 유리에는 전혀 효과를 나타내지 않았다. 그러므로 본 연구 결과는 PPD와 PPT가 경구로 투여된 인삼 추출물의 면역조절 작용을 담당하는 장내 인삼 대사체 중의 한 종류임을 제시한다.

Keywords

References

  1. Babayigit A, Olmez D, Karaman O, Bagriyanik HA, Yilmaz O, Kivcak B, Erbil G, Uzuner N. Ginseng ameliorates chronic histopathologic changes in a murine model of asthma. Allergy Asthma Proc. 29: 493-498 (2008) https://doi.org/10.2500/aap.2008.29.3137
  2. Lim YJ, Na HS, Yun YS, Choi IS, Oh JS, Rhee JH, Cho BH, Lee HC. Suppressive effects of ginsan on the development of allergic reaction in murine asthmatic model. Int Arch Allergy Immunol. 150: 32-42 (2009) https://doi.org/10.1159/000210378
  3. Sugiyama S, Shibata T, Uekawa M, Makai Y. Inhibitory effect of red ginseng on chemical mediator release from mast cells in type I allergy. The Ginseng Rev. 12: 728-731 (1991)
  4. Choo MK, Park EK, Han MJ, Kim DH. Antiallergic activity of ginseng and its ginsenosides. Planta Med. 69: 518-522 (2003) https://doi.org/10.1055/s-2003-40653
  5. Ro JY, Yoon SJ, Lee JW, Kim KH. Effects of Panax Ginseng Saponin on chemical mediator release from airway smooth muscle in actively sensitized guinea pig. Proc Int Ginseng Symposium. 84-93 (1993)
  6. Ro JY, Kim KH. The effects of single component of ginsenosides on the mechanism of mediator release in the allergic hypersensitivity. Korean J of Pharmacol. 30: 243-254 (1994)
  7. Ro JY, Ahn YS, Kim KH. Inhibitory effect of ginsenoside on the mediator release in the guinea pig lung mast cells activated by specific antigen-antibody reactions. Int J Immunopharmacol. 20: 625-641 (1998) https://doi.org/10.1016/S0192-0561(98)00062-9
  8. Lee JY, Lee YD, Bahn JW, Park HS. A case of occupational asthma and rhinitis caused by Sanyak and Korean ginseng dusts. Allergy. 61: 392-403 (2006) https://doi.org/10.1111/j.1398-9995.2006.01032.x
  9. Kim KM, Kwon HS, Jeon SG, Park CH, Sohn SW, Kim DI, Kim SS, Chang YS, Kim YK, Cho SH, Min KU, Kim YY. Korean ginseng-induced occupational asthma and determination of IgE binding components. J Korean Med Sci. 23: 232-235 (2008) https://doi.org/10.3346/jkms.2008.23.2.232
  10. Subiza J, Subiza JL, Escribano PM, Hinojosa M, Garcia R, Jerez M, Subiza E. Occupational asthma caused by Brazil ginseng dust. J Allergy Clin Immunol. 88: 731-736 (1991) https://doi.org/10.1016/0091-6749(91)90179-R
  11. Hasegawa H, Sung JH, Matsumiya S, Uchiyama M. Main ginseng saponin metabolites formed by intestinal bacteria. Planta Med. 62: 453-457 (1996) https://doi.org/10.1055/s-2006-957938
  12. Bae EA, Park SY, Kim DH. Constitutive beta-glucosidases hydrolyzing ginsenoside Rb1 and Rb2 from human intestinal bacteria. Biol Pharm Bull. 23: 1481-1485 (2000) https://doi.org/10.1248/bpb.23.1481
  13. Wakabayashi C, Hasegawa H, Murata J, Saiki I. In vivo antimetastatic action of ginseng protopanaxadiol saponins is based on their intestinal bacterial metabolites after oral administration. Oncol Res. 9: 411-417 (1997)
  14. Lee SJ, Sung JH, Moon CK, Lee BH. Antitumor activity of a novel ginseng saponin metabolite in human pulmonary adenocarcinoma cells resistant to cisplatin. Cancer Lett. 144: 39-43 (1999) https://doi.org/10.1016/S0304-3835(99)00188-3
  15. Lee SJ, Ko WG, Kim JH, Sung JH, Moon CK, Lee BH. Induction of apoptosis by a novel intestinal metabolite of ginseng saponin via cytochrome c-mediated activation of caspase-3 protease. Biochem Pharmacol. 60: 677-685 (2000) https://doi.org/10.1016/S0006-2952(00)00362-2
  16. Wakabayashi C, Murakami K, Hasegawa H, Murata J, Saiki I. An intestinal bacterial metabolite of ginseng protopanaxadiol saponins has the ability to induce apoptosis in tumor cells. Biochem Biophys Res Commun. 246: 725-730 (1998) https://doi.org/10.1006/bbrc.1998.8690
  17. Undem B, Green F, Warner T, Buckner C, Graziano FM. A procedure for isolation and partial purification guinea pig lung mast cells. J Immunol Methods. 81: 187-197 (1985) https://doi.org/10.1016/0022-1759(85)90203-0
  18. Siraganian RP. An automated continuous-flow system for the extraction and fluorometric analysis of histamine. Anal Biochem. 57: 383-394 (1974) https://doi.org/10.1016/0003-2697(74)90093-1
  19. Karikura M, Miyase T, Tanizawa H, Taniyama T, Takino Y. Studies on absorption, distribution, excretion and metabolism of ginseng saponins. VI. The decomposition products of ginsenoside Rb2 in the stomach of rats. Chem Pharm Bull (Tokyo). 39: 400-404 (1991) https://doi.org/10.1248/cpb.39.400
  20. Han BH, Park MH, Han YN, Woo LK, Sankawa U, Yahara S, Tanaka O. Degradation of Ginseng Saponins under Mild Acidic Conditions. Planta Med. 44: 146-149 (1982) https://doi.org/10.1055/s-2007-971425
  21. Sandler C, Ekokoski E, Lindstedt KA, Vainio PJ, Finel M, Sorsa T, Kovanen PT, Golub LM, Eklund KK. Chemically modified tetracycline (CMT)-3 inhibits histamine release and cytokine production in mast cells: possible involvement of protein kinase C. Inflamm Res. 54:304-312 (2005) https://doi.org/10.1007/s00011-005-1358-5
  22. Abdel-Raheem IT, Hide I, Yanase Y, Shigemoto-Mogami Y, Sakai N, Shirai Y, Saito N, Hamada FM, El-Mahdy NA, Elsisy Ael-D, Sokar SS, Nakata Y. Protein kinase C-alpha mediates TNF release process in RBL-2H3 mast cells. Br J Pharmacol. 145: 415-423 (2005) https://doi.org/10.1038/sj.bjp.0706207
  23. Schroeder JT, Howard BP, Jenkens MK, Kagey-Sobotka A, Lichtenstein LM, MacGlashan DW Jr. IL-4 secretion and histamine release by human basophils are differentially regulated by protein kinase C activation. J Leukoc Biol.63: 692-698 (1998)
  24. Hakim-Rad K, Metz M, Maurer M. Mast cells: makers and breakers of allergic inflammation. Curr Opin Allergy Clin Immunol. 9: 427-430 (2009) https://doi.org/10.1097/ACI.0b013e32832e9af1
  25. Weiss DL, Brown MA. Regulation of IL-4 production in mast cells: a paradigm for cell-type-specific gene expression. Immunol Rev. 179: 35-47 (2001) https://doi.org/10.1034/j.1600-065X.2001.790104.x
  26. Kuperman DA, Schleimer RP. Interleukin-4, interleukin-13, signal transducer and activator of transcription factor 6, and allergic asthma. Curr Mol Med. 8: 384-392 (2008) https://doi.org/10.2174/156652408785161032
  27. Romagnani S. Regulation of the T cell response. Clin Exp Allergy. 36: 1357-1366 (2006) https://doi.org/10.1111/j.1365-2222.2006.02606.x
  28. Savignac M, Badou A, Moreau M, Leclerc C, Guery JC, Paulet P, Druet P, Ragab-Thomas J, Pelletier L. Protein kinase C-mediated calcium entry dependent upon dihydropyridine sensitive channels: a T cell receptor-coupled signaling pathway involved in IL-4 synthesis. FASEB J. 15: 1577-1579 (2001)
  29. Scapini P, Lapinet-Vera JA, Gasperini S, Calzetti F, Bazzoni F, Cassatella MA. The neutrophil as a cellular source of chemokines. Immunol Rev. 177: 195-203 (2000) https://doi.org/10.1034/j.1600-065X.2000.17706.x
  30. Bertazza L, Mocellin S. Tumor necrosis factor (TNF) biology and cell death. Front Biosci. 13: 2736-2743 (2008) https://doi.org/10.2741/2881