본문 바로가기
HOME> 논문 > 논문 검색상세

논문 상세정보

Journal of ginseng research = 高麗人參學會誌 v.31 no.4, 2007년, pp.181 - 190   피인용횟수: 4

고려홍삼으로부터 분리한 compound K 함유분획에 의한 대식세포의 toll-like receptor-의존성 신호전달로 활성조절 분석
Compound K (CK) Rich Fractions from Korean Red Ginseng Inhibit Toll-like Receptor (TLR) 4- or TLR9-mediated Mitogen-activated Protein Kinases Activation and Pro-inflammatory Responses in Murine Macrophages

양철수   (충남대학교 의과대학 미생물학교실UU0001302  ); 고성룡   (KT&G 중앙연구소CC0187146  ); 조병구   (KT&G 중앙연구소CC0187146  ); 이지연   (충남대학교 의과대학 미생물학교실UU0001302  ); 김기혜   (충남대학교 의과대학 미생물학교실UU0001302  ); 신동민   (충남대학교 의과대학 미생물학교실UU0001302  ); 육재민   (충남대학교 의과대학 미생물학교실UU0001302  ); 손현수   (KT&G 중앙연구소CC0187146  ); 김영숙   (KT&G 중앙연구소CC0187146  ); 위재준   (KT&G 중앙연구소CC0187146  ); 도재호   (KT&G 중앙연구소CC0187146  ); 조은경   (충남대학교 의과대학 미생물학교실UU0001302  );
  • 초록

    본 연구에서는 고려홍삼으로부터 새로 분리한 CK 함유분획을 이용하여 마우스 대식세포에 대한 선천면역반응 조절에 미치는 영향을 조사하였다. 본 연구에서 사용된 농도의 CK 함유분획에서는 세포독성 효과가 관찰되지 않았으며 CK함유 분획의 전처리에 의하여 그람음성세균의 LPS, 또는 CpG-ODN에 의해 유도되는 NF- ${\kappa}B$ 와 MAPK 활성 및 전염증성 사이토카인, NO의 분비가 TLR4 및 TLR9 특이적으로 억제되었다. 이와 같은 결과는 CK 함유분획이 TLR4을 매개로하는 염증반응뿐만 아니라 TLR9을 통한 염증반응에도 영향을 미치는 것으로 해석된다. 따라서 앞으로 CK 함유 분획에 포함된 개별 사포닌 등 시료 성분에 대한 면밀한 분석, 그리고 이들 개별 물질이 각각의 신호전달 체계에 미치는 영향과 그 기작에 대한 연구가 더욱 필요할 것으로 사료되며 염증억제제로서의 개발 가능성을 탐구하기 위한 생체 내에서의 효능 및 작용기전 분석이 요구된다.


    Compound K (CK), a protopanaxadiol ginsenoside metabolite, was previously shown to have immunomodulatory effects. In this study, we isolated the CK rich fractions (CKRF) from Korean Red Ginseng and investigated the regulation of CKRF-mediated inflammatory signaling during Toll-like receptor (TLR)-mediated cellular activation. Among various TLR ligands, CKRF considerably abrogated TLR4- or TLR9-induced inflammatory signaling. Both LPS and CpG-containing oligodeoxynucleotides (CpG-ODN) stimulation rapidly activates mitogen-activated protein kinases [MAPKs; extracellular signal-regulated kinases 1/2 and p38], NF- ${\kappa}B$ , and expression of pro-inflammatory cytokines tumor necrosis factor- ${\alpha}$ , and interleukin-6 in murine bone marrow-derived macrophages (BMDMs) in a time- and dose-dependent manner. Of interest, pre-treatment of CKRF in either LPS/TLR4- or CpG-ODN/TLR9-stimulated macrophages substantially attenuated the LPS-induced inflammatory cytokine production and mRNA expressions, as well as MAPK and NF- ${\kappa}B$ activation. To our knowledge, this is the first description of the inhibitory roles for CKRF in TLR4- or TLR9-associated signaling in BMDMs. Collectively, these results demonstrate that CKRF specifically modulates distinct TLR4 and TLR9-mediated inflammatory responses, and further studies are urgently needed for their in vivo roles for potential therapeutic uses, such as in systemic inflammatory syndromes.


  • 주제어

    Compound K-rich fractions .   Toll-like receptors .   Mitogen-activated protein kinases .   Inflammation.  

  • 참고문헌 (38)

    1. Park, M. G. : Korean ginseng. Korea Ginseng and Tobacco Research Institute, Seoul Korea, p.63 (1994) 
    2. Park, C. K., Jeon, B. S. and Yang, J. W.: The chemical components of Korean Ginseng. Korean J. Food & Nutr. 8, 10- 23 (2003) 
    3. Kawai, T. and Akira, S.: TLR signaling. Cell Death Differ. 13, 816-25 (2006) 
    4. Takeuchi, O., Sato, S., Horiuchi, T., Hoshino, K., Takeda, K., Dong, Z., Modlin, R. L. and Akira, S.: Cutting edge: Role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J. Immunol. 169, 10-14 (2002) 
    5. Alexopoulou, L., Holt, A. C., Medzhitov, R. and Flavell, R. A.: Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 413, 732-738 (2001) 
    6. Paqurt, P. and Pierard, G. E.: Interleukin-6 and the skin. Int.Arch. Allergy Immunol. 109, 308-317 (1996) 
    7. Takeuchi, O., Hoshino. K., Kawai, T., Sanjo, H., Takada, K., Oqawa, T., Takeda, K. and Akira, S.: Differential roles of TLR2 and TLR4 in recognition of gram-negative and grampositive bacterial cell wall components. Immunity. 11, 443- 451 (1999) 
    8. Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., Matsumoto, M., Hoshino, K., Wagner, H., Takeda, K. and Akira, S.: A Toll-like receptor recognizes bacterial DNA. Nature. 408, 740-745 (2000) 
    9. Wieland, C. W., Florquin, S., Maris, N. A., Hoebe, K., Beutler, B., Takeda, K., Akira, S. and van der Poll, T.: The MyD88-dependent, but not the MyD88-independent, pathway of TLR4 signaling is important in clearing nontypeable haemophilus influenzae from the mouse lung. J. Immunol. 175, 6042-6049 (2005) 
    10. Chi, H., Kim, D. H. and Ji, G. E.: Transformation of Ginsenosides Rb2 and Rc from Panax ginseng by Food Microorganisms. Biol. Pharm. Bull. 28, 2102-2105 (2005) 
    11. Jun, S. H., Woo, M. S., Kim, S. Y., Kim, W. K., Hyun, J. W., Kim, E. J., Kim, D. H. and Kim, H. S.: Ginseng saponin metabolite suppresses phorbol ester-induced matrix metalloproteinase- 9 expression through inhibition of activator protein-1 and mitogen-activated protein kinase signaling pathways in human astroglioma cells. Int. J. Cancer. 118, 490-497 (2006) 
    12. Paek, I. B., Moon, Y., Kim, J., Ji, H.Y., Kim, S.A., Sohn, D.H., Kim, J.B. and Lee, H.S.: Pharmacokinetics of a ginseng saponin metabolite compound K in rats. Biopharm. Drug. Dispos. 27, 39-45 (2006) 
    13. Ding, A. H., Nathan, C. F. and Stuehr, D. J.: Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. J. Immunol. 141, 2407-2412 (1988) 
    14. Keum, Y. S., Han, S. S., Chun, K. S., Park, K. K., Park, J. H., Lee, S. K. and Surh, Y. J.: Inhibitory effects of the ginsenoside Rg3 on phorbol ester-induced cyclooxygenase-2 expression, NF-kappaB activation and tumor promotion. Mutat. Res. 523-524, 75-85 (2003) 
    15. Zhang, Q., Kang, X. and Zhao, W.: Antiangiogenic effect of low dose cyclophosphamide combined with ginsenoside Rg3 on Lewis lung carcinoma. Biochem. Biophys. Res. Commun. 342, 824-828 (2006) 
    16. Wu, C. F., Bi, X. L., Yang, J. Y., Zhan, J. Y., Dong, Y. X., Wang, J. H., Wang, J. M., Zhang, R. and Li, X.: Differential effects of ginsenosides on NO and TNF-alpha production by LPSactivated N9 microglia. Int. Immunopharmacol. 7, 313-320 (2007) 
    17. Wang, T., Lafuse, W. P. and Zwilling, B. S.: NFkappaB and Sp1 elements are necessary for maximal transcription of toll-like receptor 2 induced by Mycobacterium avium. J.Immunol. 167, 6924-6932 (2001) 
    18. Pathak, S. K., Bhattacharyya, A., Pathak, S., Basak, C., Mandal, D., Kundu, M. and Basu, J.: Toll-like receptor 2 and mitogen- and stress-activated kinase 1 are effectors of Mycobacterium avium-induced cyclooxygenase-2 expression in macrophages. J. Biol. Chem. 279, 55127-55136 (2004) 
    19. Pennini, M. E., Pai, R. K., Schultz, D. C., Boom, W. H. and Harding, C. V.: Mycobacterium tuberculosis 19-kDa lipoprotein inhibits IFN-gamma-induced chromatin remodeling of MHC2TA by TLR2 and MAPK signaling. J. Immunol. 176, 4323-4330 (2006) 
    20. Surewicz, K., Aung, H., Kanost, R. A., Jones, L., Hejal, R. and Toossi, Z.: The differential interaction of p38 MAP kinase and tumor necrosis factor-alpha in human alveolar macrophages and monocytes induced by Mycobacterium tuberculosis. Cell Immunol. 228, 34-41 (2004) 
    21. Hasan, Z., Shah, B. H., Mahmood, A., Young, D. B. and Hussain, R.: The effect of mycobacterial virulence and viability on MAP kinase signaling and TNF alpha production by human monocytes. Tuberculosis (Edinb.). 83, 299-309 (2003) 
    22. Song, C. H., Lee, J. S., Lee, S. H., Lim, K., Kim, H. J., Park, J. K., Paik, T.H. and Jo, E. K.: Role of mitogen-activated protein kinase pathways in the production of tumor necrosis factor-alpha, interleukin-10, and monocyte chemotactic protein- 1 by Mycobacterium tuberculosis H37Rv-infected human monocytes. J. Clin. Immunol. 23, 194-201 (2003) 
    23. Yang, C. S., Lee, J. S., Jung, S. B., Oh, J. H., Song, C. H., Kim, H. J., Park, J. K., Paik, T. H. and Jo, E. K.: Differential regulation of interleukin-12 and tumour necrosis factoralpha by phosphatidylinositol 3-kinase and ERK 1/2 pathways during Mycobacterium tuberculosis infection. Clin. Exp. Immunol. 143, 150-160 (2006) 
    24. Yang, C. S., Song, C. H., Lee, J. S., Jung, S. B., Oh, J. H., Kim, H. J., Park, J. K., Paik, T. H. and Jo, E. K.: Intracellular network of phosphatidylinositol 3-kinase, mammalian target of the rapamycin/70 kDa ribosomal S6 kinase 1, and mitogen- activated protein kinases pathways for regulating mycobacteria-induced IL-23 expression in human macrophages. Cell Microbiol. 8, 1158-1171 (2006) 
    25. Jo, E. K., Yang, C. S., Choi, C. H. and Harding, C. V.: Intracellular signalling cascades regulating innate immune responses to Mycobacteria: branching out from Toll-like receptors. Cellular Microbiology. 9, 1087-1098 (2007) 
    26. Balkwill, F. R.: Tumour necrosis factor. Br. Med. Bull. 45, 389-400 (1989) 
    27. Flynn, J. L., Goldstein, M. M., Chan, J., Triebold, K. J., Pfeffer, K., Lowenstein, C. J., Schreiber, R., Mak, T. W. and Bloom, B. R.: Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity. 2, 561-572 (1995) 
    28. Liew, F. Y., Li, Y. and Millott, S.: Tumor necrosis factor-$\alpha$ synergizes with IFN-${\gamma}$ in mediating killing of Leishmania major through the induction of nitric oxide. J. Immunol. 145, 4306-4310 (1990) 
    29. Jones, A. L. and Selby, P.: Clinical applications of tumour necrosis factor. Prog Growth Factor Res. 1, 107-122 (1989) 
    30. Chew, C. H., Chew, G. S., Najimudin, N. and Tengku- Muhammad, T. S.: Interleukin-6 inhibits human peroxisome proliferator activated receptor alpha gene expression via CCAAT/enhancer-binding proteins in hepatocytes. J. Biochem. Cell Biol. In press (2007) 
    31. Sparwasser, T., Miethke, T., Lipford, G., Borschert, K., Hacker, H., Heeg, K. and Wagner, H.: Bacterial DNA causes septic shock. Nature. 386, 336-337 (1997) 
    32. Yi, A. K., Tuetken, R., Redford, T., Waldschmidt, M., Kirsch, J. and Krieg, A. M.: CpG motifs in bacterial DNA activate leukocytes through the pH-dependent generation of reactive oxygen species. J. Immunol. 160, 4755-4761 (1998) 
    33. Kobayashi, K., Hernandez, L. D., Galan, J. E., Janeway, C. A., Jr Medzhitov, R. and Flavell, R. A.: IRAK-M is a negative regulator of toll-like receptor signaling. Cell. 110, 191-202 (2002) 
    34. Hacker, H., Vabulas, R. M., Takeuchi, O., Hoshino, K., Akira, S. and Wagner, H.: Immune cell activation by bacterial CpGDNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF) 6. J. Exp. Med. 192, 595-600 (2000) 
    35. Chu, W., Gong, X., Li, Z., Takabayashi, K., Ouyang, H., Chen, Y., Lois, A., Chen, D. J., Li, G. C., Karin, M. and Raz, E.: DNA-PKcs is required for activation of innate immunity by immunostimulatory DNA. Cell. 103, 909-918 (2000) 
    36. Kindler, V., Sappino, A. P., Grau, G. E., Piguet, P. F. and Vassalli, P.: The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell. 56, 731-740 (1989) 
    37. Klinman, D. M., Takeshita, F., Gursel, I., Leifer, C., Ishii, K. J., Verthelyi, D. and Gursel, M.: CpG DNA: recognition by and activation of monocytes. Microbes Infect. 4, 897-901 (2002) 
    38. Slotta, J. E., Scheuer, C., Menger, M. D. and Vollmar, B.: Immunostimulatory CpG-oligodeoxynucleotides (CpG-ODN) induce early hepatic injury, but provide a late window for protection against endotoxin-mediated liver damage. J. Hepatol. 44, 576-585 (2006) 
  • 이 논문을 인용한 문헌 (4)

    1. 2008. "" Journal of ginseng research = 高麗人參學會誌, 32(4): 315~323     
    2. Choi, Jae-Ho ; Oh, Deog-Hwan 2009. "Effect of White and Red Ginseng Extracts on the Immunological Activities in Lymphocytes Isolated from Sasang Constitution Blood Cells" Journal of ginseng research = 高麗人參學會誌, 33(1): 33~39     
    3. Park, Hye-Jin ; Jung, Da-Hye ; Joo, Hae-Mi ; Kang, Nam-Sung ; Jang, Seon-A ; Lee, Jae-Geun ; Sohn, Eun-Hwa 2010. "The comparative study of anti-allergic and anti-inflammatory effects by fermented red ginseng and red ginseng" 韓國資源植物學會誌 = Korean journal of plant resources, 23(5): 415~422     
    4. Jeong, Su-Ji ; Kim, Kyoung-Hee ; Son, Hwa-Young ; Yook, Hong-Sun 2014. "Effects of Extract from Fermented Flower-buds of Panax ginseng C.A. Meyer on Mouse Cytokine IL-6, TNF-α Production" 한국식품영양학회지 = The Korean journal of food and nutrition, 27(1): 43~49     

 저자의 다른 논문

  • 양철수 (4)

    1. 2005 "Mycobacteria-induced Interleukin-12 Expression by Human Monocyte-derived Macrophages Is Negatively Regulated by Phosphatidylinositol 3-kinase and ERK 1/2 Pathways" Journal of bacteriology and virology : JBV 35 (3): 239~248    
    2. 2005 "사람 단핵구에서 결핵균에 의해 유도되는 CCL3 및 CCL4 발현에 대한 Phospholipase-Protein Kinase C-MEK-ERK 경로의 역할 분석" Immune network : official journal of the Korean association of immunobiologists 5 (4): 237~246    
    3. 2006 "저산소 분압과 낮은 산도 조건에서 발현이 증가되는 결핵균 단백질의 동정" Journal of bacteriology and virology : JBV 36 (2): 59~68    
    4. 2009 "Nitric Oxide Synthesis is Modulated by 1,25-Dihydroxyvitamin D3 and Interferon-${\gamma}$ in Human Macrophages after Mycobacterial Infection" Immune network : official journal of the Korean association of immunobiologists 9 (5): 192~202    
  • 고성룡 (2)

  • 이지연 (0)

  • 김기혜 (0)

  • 신동민 (1)

  • Yuk, Jae-Min (4)

  • 김영숙 (3)

  • 도재호 (16)

  • Jo, Eun-Kyeong (32)

 활용도 분석

  • 상세보기

    amChart 영역
  • 원문보기

    amChart 영역

원문보기

무료다운로드
  • NDSL :
유료다운로드

유료 다운로드의 경우 해당 사이트의 정책에 따라 신규 회원가입, 로그인, 유료 구매 등이 필요할 수 있습니다. 해당 사이트에서 발생하는 귀하의 모든 정보활동은 NDSL의 서비스 정책과 무관합니다.

원문복사신청을 하시면, 일부 해외 인쇄학술지의 경우 외국학술지지원센터(FRIC)에서
무료 원문복사 서비스를 제공합니다.

NDSL에서는 해당 원문을 복사서비스하고 있습니다. 위의 원문복사신청 또는 장바구니 담기를 통하여 원문복사서비스 이용이 가능합니다.

이 논문과 함께 이용한 콘텐츠
이 논문과 함께 출판된 논문 + 더보기