Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Compound K Rich Fractions Regulate NF-κB-dependent Inflammatory Responses and Protect Mice from Endotoxin-induced Lethal Shock

  • Yang, Chul-Su (Department of Microbiology and Infection Signaling Network Research Center) ;
  • Yuk, Jae-Min (Department of Microbiology and Infection Signaling Network Research Center) ;
  • Ko, Sung-Ryong (Ginseng Research Group, KT&G Central Research Institute) ;
  • Cho, Byung-Goo (Ginseng Research Group, KT&G Central Research Institute) ;
  • Sohn, Hyun-Joo (Ginseng Research Group, KT&G Central Research Institute) ;
  • Kim, Young-Sook (Ginseng Research Group, KT&G Central Research Institute) ;
  • Wee, Jae-Joon (Ginseng Research Group, KT&G Central Research Institute) ;
  • Do, Jae-Ho (Ginseng Research Group, KT&G Central Research Institute) ;
  • Jo, Eun-Kyeong (Department of Microbiology and Infection Signaling Network Research Center)
  • Published : 2008.12.31
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Abstract

In the previous studies, we isolated the compound K rich fractions (CKRF) and showed that CKRF inhibited Toll-like receptor (TLR) 4- or TLR9-induced inflammatory signaling. To extend our previous studies,1) we investigated the molecular mechanisms of CKRF in the TLR4-associated signaling via nuclear factor (NF)-${\kappa}B$, and in vivo role of CKRF for induction of tolerance in lipopolysaccharide (LPS)-induced septic shock. In murine bone marrow-dervied macrophages, CKRF significantly inhibited the induction of mRNA expression of proinflammatory mediators such as tumor necrosis factor-${\alpha}$, interleukin-6, cyclooxygenase-2, and inducible nitric oxide synthase. In addition, CKRF significantly attenuated the transcriptional activities of TLR4/LPS-induced NF-${\kappa}B$. Nuclear translocation of NF-${\kappa}B$ in response to LPS stimulation was significantly abrogated by pre-treatment with CKRF. Furthermore, CKRF inhibited the recruitment of p65 to the interferon-sensitive response element flanking region in response to LPS. Finally, oral administration of CKRF significantly protected mice from Gram-negative bacterial LPS-induced lethal shock and inhibited systemic inflammatory cytokine levels. Together, these results demonstrate that CKRF modulates the TLR4-dependent NF-${\kappa}B$ activation, and suggest a therapeutic role for Gram-negative septic shock.

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References

  1. Yang, C. S., Ko, S. R., Cho, B. G., Lee, J. Y., Kim, K. H., Shin, D. M., Yuk, J. M., Sohn, H. J., Kim, Y. S., Wee, J. J., Do, J. H. and Jo, E. K. : 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. J. Ginseng Res. 31, 181-190 (2007) https://doi.org/10.5142/JGR.2007.31.4.181
  2. Carpenter, S. and O'Neill, L. A. : How important are Toll-like receptors for antimicrobial responses? Cell. Microbiol. 9, 1891-901 (2007) https://doi.org/10.1111/j.1462-5822.2007.00965.x
  3. Takeda, K. and Akira, S. : Toll-like receptors in innate immunity. Int Immunol. 17, 1-14 (2005)
  4. Jo, E. K., Yang, C. S., Choi, C. H. and Harding, C. V. : Intracellular signaling cascades regulating innate immune responses to Mycobacteria: branching out from Toll-like receptors. Cell. Microbiol. 9, 1087-1098 (2007) https://doi.org/10.1111/j.1462-5822.2007.00914.x
  5. Hunter, P. : Sepsis under siege: a new understanding of sepsis might lead to the development of therapies to treat septic shock. EMBO Rep. 7, 667-669 (2006) https://doi.org/10.1038/sj.embor.7400742
  6. Fitzgerald, K. A., Palsson-McDermott, E. M., Bowie, A. G., Jefferies, C. A., Mansell, A. S., Brady, G., Brint, E., Dunne, A., Gray, P., Harte, M. T., McMurray, D., Smith, D. E., Sims, J. E., Bird, T. A. and O'Neill, L. A. : Mal (MyD88-adapterlike) is required for Toll-like receptor-4 signal transduction. Nature. 413, 78-83 (2001) https://doi.org/10.1038/35092578
  7. Fitzgerald, K. A., Rowe, D. C., Barnes, B. J., Caffrey, D. R., Visintin, A., Latz, E., Monks, B., Pitha, P. M. and Golenbock, D.T. : LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J Exp Med. 198, 1043-1055 (2003) https://doi.org/10.1084/jem.20031023
  8. Cohen, J. : The immunopathogenesis of sepsis. Nature. 420, 885-891 (2002) https://doi.org/10.1038/nature01326
  9. Yang, C. S., Lee, D. S., Song, C. H., An, S. J., Li, S., Kim, J. M., Kim, C. S., Yoo, D. G., Jeon, B. H., Yang, H. Y., Lee, T. H., Lee, Z. W., El-Benna, J., Yu, D. Y. and Jo, E. K. : Roles of peroxiredoxin II in the regulation of proinflammatory responses to LPS and protection against endotoxin-induced lethal shock. J Exp Med. 204, 583-594 (2007) https://doi.org/10.1084/jem.20061849
  10. Yang, C. S., Ko, S. R., Cho, B. G., Shin, D. M., Yuk, J. M., Li, S., Kim, J. M., Evans, R. M., Jung, J. S., Song, D. K. and Jo, E. K. : The Ginsenoside Metabolite Compound K, a Novel Agonist of Glucocorticoid Receptor, Induces Tolerance to Endotoxin-induced Lethal Shock. J. Cell. Mol. Med. 12, 1739-1753 (2008) https://doi.org/10.1111/j.1582-4934.2007.00181.x
  11. Li, Y. N., Wu, Y. L., Jia, Z. H. and Qi, J. S.: Interaction between COX-2 and iNOS aggravates vascular lesion and antagonistic effect of ginsenoside. J. Ethnopharmacol. 119, 305-311 (2008) https://doi.org/10.1016/j.jep.2008.07.018
  12. Seo, Y. J., Kwon, M. S., Choi, H. W., Jang, J. E., Lee, J. K., Sun, Y., Jung, J. S., Park, S. H. and Suh, H.W. : Intracerebroventricular ginsenosides are antinociceptive in proinflammatory cytokine-induced pain behaviors of mice. Arch Pharm. Res. 31, 364-369 (2008) https://doi.org/10.1007/s12272-001-1165-x
  13. Bae, E. A., Kim, N. Y., Han, M. J., Choo, M. K. and Kim, D. H. : Transformation of ginsenoside to compound K (IH-901) by lactic acid bacteria of human intestine. J. Microbiol. Biotechnol. 13, 9-14 (2003)
  14. Jiang, B. H., Han, Y., Zhao, Y. Q., Hu, X. M. and Zheng, L. X. : Optimization of enzymatic translation for preparation ginsenoside compound K in total saponins of Panax notoginseng. Chin. Tradit. Herb Drugs. 35, 986-988 (2004)
  15. Hasegawa, H., Sung, J. H. and Hur, J. D. : Ginseng intestinal bacterial metabolite IH901 as a new antimetastatic agent. Arch. Pharm. Res. 20, 539-544 (1997) https://doi.org/10.1007/BF02975208
  16. Bae, E. A., Choo, M. K., Park, E. K., Park, S. Y., Shin, H. Y. and Kim, D. H. : Metabolism of ginsenoside R(c) by human intestinal bacteria and its related antiallergic activity. Biol. Pharm. Bull. 25, 743-747 (2002) https://doi.org/10.1248/bpb.25.743
  17. Park, E. J., Zhao, Y. Z., Kim, J. and Sohn, D. H. : A ginsenoside metabolite, 20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol, triggers apoptosis in activated rat hepatic stellate cells via caspase-3 activation. Planta Med. 72, 1250-1253 (2006) https://doi.org/10.1055/s-2006-947223
  18. Yoon, S. H., Han, E. J., Sung, J. H. and Chung, S. H. : Antidiabetic effects of compound K versus metformin versus compound K-metformin combination therapy in diabetic db/db mice. Biol. Pharm. Bull. 30, 2196-2200 (2007) https://doi.org/10.1248/bpb.30.2196
  19. Akira, S. and Hoshino, K. : Myeloid differentiation factor 88-dependent and -independent pathways in Toll-like receptor signaling. J. Infect. Dis. 187, S356-S363 (2003) https://doi.org/10.1086/374749
  20. Akira, S. and Takeda, K. : Toll-like receptor signaling. Nat. Rev. Immunol. 4, 499-511 (2004) https://doi.org/10.1038/nri1391
  21. Ogawa, S., Lozach, J., Benner, C., Pascual, G., Tangirala, R. K., Westin, S., Hoffmann, A., Subramaniam, S., David, M., Rosenfeld, M. G. and Glass, C. K. : Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell. 122, 707-721 (2005) https://doi.org/10.1016/j.cell.2005.06.029
  22. Toshchakov, V., Jones, B. W., Perera, P. Y., Thomas, K., Cody, M. J., Zhang, S., Williams, B. R., Major, J., Hamilton, T. A., Fenton, M. J. and Vogel, S. N. : TLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages. Nat Immunol. 3, 392-398 (2002) https://doi.org/10.1038/ni774
  23. Bernard, R., Vincent, J. L., Laterre, P. F., LaRosa, S. P., Dhainaut, J. F., Lopez-Rodriguez, A., Steingrub, J. S., Garber, G. E., Helterbrand, J. D., Ely, E. W. and Fisher, C. J. : Efficacy and safety of recombinant human activated protein C for severe sepsis. N. Engl. J. Med. 344, 699-709 (2001) https://doi.org/10.1056/NEJM200103083441001
  24. Imahara, S. D. and O'Keefe, G. E. : Genetic determinants of the inflammatory response. Curr. Opin. Crit. Care 10, 318-324 (2004) https://doi.org/10.1097/01.ccx.0000140942.42247.7e
  25. Weighardt, H. and Holzmann, B. : Role of Toll-like receptor responses for sepsis pathogenesis Immunobiology. 212, 715-722 (2008) https://doi.org/10.1016/j.imbio.2007.09.010
  26. Raynauud, P. and Ojasoo, T. : The design and use of sex-steroid antagonists, J. Steroid Biochem. 25, 811-833 (1986) https://doi.org/10.1016/0022-4731(86)90313-4
  27. Bratoeff, E., Ramírez, E., Flores, E., Sánchez, M., Heuze, I. and Cabeza, M. : New aromatic esters of progesterone as antiandrogens, J. Enz. Inh. Med. Chem. 19, 99-105 (2004) https://doi.org/10.1080/14756360310001650246
  28. Li, H., Lee, J. H. and Ha, J. M. : Effective purification of ginsenosides from cultured wild ginseng roots, red ginseng, and white ginseng with macroporous resins. J. Microbiol. Biotechnol. 18, 1789-1791 (2008)
  29. Joo, S. S., Yoo, Y. M., Ahn, B. W., Nam, S. Y., Kim, Y. B., Hwang, K. W. and Lee, do. I. : Prevention of inflammationmediated neurotoxicity by Rg3 and its role in microglial activation. Biol Pharm Bull. 31, 1392-1396 (2008) https://doi.org/10.1248/bpb.31.1392
  30. Yang, Z. G., Sun, H. X. and Ye, Y. P. : Ginsenoside Rd from Panax notoginseng is cytotoxic towards HeLa cancer cells and induces apoptosis. Chem Biodivers. 3, 187-197 (2006) https://doi.org/10.1002/cbdv.200690022
  31. Park, E. K., Shin, Y. W., Lee, H. U., Kim, S. S., Lee, Y. C., Lee, B. Y. and Kim, D. H. : Inhibitory effect of ginsenoside Rb1 and compound K on NO and prostaglandin E2 biosyntheses of RAW264.7 cells induced by lipopolysaccharide. Biol Pharm Bull. 28, 652-566 (2005) https://doi.org/10.1248/bpb.28.652
  32. De Bosscher, K., Vanden Berghe, W. and Haegeman, G. : The interplay between the glucocorticoid receptor and nuclear factor-kappaB or activator protein-1: molecular mechanisms for gene repression. Endocr. Rev. 24, 488-522 (2003) https://doi.org/10.1210/er.2002-0006
  33. Ye, X., Ding, J., Zhou, X., Chen, G. and Liu, S. F. : Divergent roles of endothelial NF-kappaB in multiple organ injury and bacterial clearance in mouse models of sepsis. J. Exd. Med. 9, 1303-1315 (2008)
  34. Liu, S. F. and Malik, A. B. : NF-${\kappa}B$ activation as a pathologic mechanism of septic shock and inflammation. Am. J. Physiol. Lung Cell. Mol. Physiol. 290, L622-L645 (2006) https://doi.org/10.1152/ajplung.00477.2005
  35. Brown, M. A. and Jones, W. K. : NF-kappaB action in sepsis: the innate immune system and the heart. Front. Biosci. 1, 1201-1217 (2004)
  36. Arnalich, F., Garcia-Palomero, E., Lopez, J., Jimenez, M., Madero, R., Renart, J., Vazquez, J. J. and Montiel, C. : Predictive value of nuclear factor kappaB activity and plasma cytokine levels in patients with sepsis. Infect. Immun. 68, 1942-1945 (2000) https://doi.org/10.1128/IAI.68.4.1942-1945.2000
  37. Choi, M., Rolle, S., Wellner, M., Cardoso, M. C., Scheidereit, C., Luft, F. C. and Kettritz, R. : Inhibition of NF-kappaB by a TAT-NEMO-binding domain peptide accelerates constitutive apoptosis and abrogates LPS-delayed neutrophil apoptosis. Blood. 102, 2259-2267 (2003) https://doi.org/10.1182/blood-2002-09-2960
  38. Savill, J. S., Wyllie, A. H., Henson, J. E., Walport, M. J., Henson, P. M. and Haslett, C. : Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages. J. Clin. Invest. 83, 865-875 (1989) https://doi.org/10.1172/JCI113970