Korean Journal of Food Science and Technology (한국식품과학회지)

Korean Society of Food Science and Technology (한국식품과학회)
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Suppression of the Expression of Cyclooxygenase-2 Induced by Toll-like Receptor 2, 3, and 4 Agonists by 6-Shogaol

6-Shogaol의 Toll-like receptor 2, 3, 4 agonists에 의해서 유도된 cyclooxygenase-2 발현 억제

  • Kim, Jeom-Ji (Department of Medical Biotechnology, College of Medical Sciences, SoonChunHyang University) ;
  • An, Sang-Il (Department of Biomedical Laboratory Science, College of Medical Sciences, SoonChunHyang University) ;
  • Lee, Jeon-Su (Department of Biomedical Laboratory Science, College of Medical Sciences, SoonChunHyang University) ;
  • Yun, Sae-Mi (Department of Biomedical Laboratory Science, College of Medical Sciences, SoonChunHyang University) ;
  • Lee, Mi-Yeong (Department of Medical Biotechnology, College of Medical Sciences, SoonChunHyang University) ;
  • Yun, Hyeong-Seon (Department of Biomedical Laboratory Science, College of Medical Sciences, SoonChunHyang University)
  • 김점지 (순천향대학교 의료과학대학 의료생명공학과) ;
  • 안상일 (순천향대학교 의료과학대학 임상병리학과) ;
  • 이전수 (순천향대학교 의료과학대학 임상병리학과) ;
  • 윤새미 (순천향대학교 의료과학대학 임상병리학과) ;
  • 이미영 (순천향대학교 의료과학대학 의료생명공학과) ;
  • 윤형선 (순천향대학교 의료과학대학 임상병리학과)
  • Published : 2008.06.30
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Abstract

Ginger is widely used as a traditional herbal medicine. Both ginger and its extracts have been used to treat many chronic inflammatory conditions via the inhibition of nuclear factor-kappa B (NF-${\kappa}B$) activation, which results in the suppression of cyclooxygenase-2 (COX-2) expression. However, the mechanisms as to how ginger extracts mediate their health effects are largely unknown. Toll-like receptors (TLRs) trigger anti-microbial innate immune responses, recognizing conserved microbial structural molecules that are known as pathogen-associated molecular patterns. All TLR signaling pathways culminate in the activation of NF-${\kappa}B$. The activation of NF- ${\kappa}B$ leads to the induction of inflammatory gene products, including cytokines and COX-2. This study reports the biochemical evidence that 6-shogaol, an active compound in ginger, inhibits NF-${\kappa}B$ activation and COX-2 expression induced by TLR2, TLR3, and TLR4 agonists. Furthermore, 6-shogaol inhibited NF-${\kappa}B$ activation induced by the following downstream signaling components of the TLRs: MyD88, $IKK{\beta}$, and p65. These results imply that ginger can modulate immune responses that could potentially modify the risk of many chronic inflammatory diseases.

선천성 면역은 병원성균의 침입에 대항하기 위한 숙주의 최초 방어체계라 할 수 있다. 이러한 선천성 면역반응은 병원균들이 가지고 있는 독특한 구조를 인식하는 TLRs에 의해서 조절되어 진다고 알려져 있다. 숙주에 침입한 여러 병원성균들이 TLRs를 자극하며 이렇게 자극된 신호들은 아래로 전달되어 전사요소 $NF-{\kappa}B$의 활성화를 유도하고 결국 COX-2와 같은 염증 유발인자를 유도하여 암이나 질병을 유발하게 된다. 우리는 이번 연구를 통하여 생강 추출물중의 하나인 6-shogaol이 어떻게 $NF-{\kappa}B$ 활성화나 COX-2 발현을 조절하여 항염증 효과를 가지고 있는지를 알아보았다. 6-shogaol은 TLR2, TLR3, TLR4 agonists에 의해서 유도된 $NF-{\kappa}B$ 활성화와 COX-2 발현을 억제하였다. 이러한 결과는6-shogaol이 여러 병원균들로부터 유도되는 염증반응이나 만성적인 질병들을 조절할 수 있다는 중요한 결과를 보여주는 것이라 할 수 있다.

Keywords

References

  1. Afzal M, Al-Hadidi D, Menon M, Pesek J, Dhami MS. Ginger: An ethnomedical, chemical and pharmacological review. Drug Metab. Drug Interact. 18: 159-190 (2001)
  2. Chang CP, Chang JY, Wang FY, Chang JG. The effect of Chinese medicinal herb Zingiberis rhizoma extract on cytokine secretion by human peripheral blood mononuclear cells. J. Ethnopharmacol. 48: 13-19 (1995) https://doi.org/10.1016/0378-8741(95)01275-I
  3. Ippoushi K, Azuma K, Ito H, Horie H, Higashio H. [6]-Gingerol inhibits nitric oxide synthesis in activated J774.1 mouse macrophages and prevents peroxynitrite-induced oxidation and nitration reactions. Life Sci. 73: 3427-3437 (2003) https://doi.org/10.1016/j.lfs.2003.06.022
  4. Thomson M, Al-Qattan KK, Al-Sawan SM, Alnaqeeb MA, Khan I, Ali M. The use of ginger (Zingiber officinale Rosc.) as a potential anti-inflammatory and antithrombotic agent. Prostag. Leukotr. Ess. 67: 475-478 (2002) https://doi.org/10.1054/plef.2002.0441
  5. Surh YJ. Anti-tumor promoting potential of selected spice ingredients with antioxidative and anti-inflammatory activities: A short review. Food Chem. Toxicol. 40: 1091-1097 (2002) https://doi.org/10.1016/S0278-6915(02)00037-6
  6. Altman RD, Marcussen KC. Effects of a ginger extract on knee pain in patients with osteoarthritis. Arthritis Rheum. 44: 2531-2538 (2001) https://doi.org/10.1002/1529-0131(200111)44:11<2531::AID-ART433>3.0.CO;2-J
  7. Kiuchi F, Iwakami S, Shibuya M, Hanaoka F, Sankawa U. Inhibition of prostaglandin and leukotriene biosynthesis by gingerols and diarylheptanoids. Chem. Pharm. Bull. 40: 387-391 (1992) https://doi.org/10.1248/cpb.40.387
  8. Tjendraputra E, Tran VH, Liu-Brennan D, Roufogalis BD, Duke CC. Effect of ginger constituents and synthetic analogues on cyclooxygenase-2 enzyme in intact cells. Bioorg. Chem. 29: 156-163 (2001) https://doi.org/10.1006/bioo.2001.1208
  9. Takeda K, Akira S. Toll-like receptors in innate immunity. Int. Immunol. 17: 1-14 (2005)
  10. Medzhitov R. Toll-like receptors and innate immunity. Nat. Rev. Immunol. 1: 135-145 (2001) https://doi.org/10.1038/35100529
  11. O'Neill LA. TLRs: Professor Mechnikov, sit on your hat. Trends Immunol. 25: 687-693 (2004) https://doi.org/10.1016/j.it.2004.10.005
  12. Vogel SN, Fitzgerald KA, Fenton MJ. TLRs: Differential adapter utilization by toll-like receptors mediates TLR-specific patterns of gene expression. Mol. Interv. 3: 466-477 (2003) https://doi.org/10.1124/mi.3.8.466
  13. Meylan E, Burns K, Hofmann K, Blancheteau V, Martinon F, Kelliher M, Tschopp J. RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. Nat. Immunol. 5: 503-507 (2004) https://doi.org/10.1038/ni1061
  14. Sato S, Sugiyama M, Yamamoto M, Watanabe Y, Kawai T, Takeda K, Akira S. Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling. J. Immunol. 171: 4304-4310 (2003) https://doi.org/10.4049/jimmunol.171.8.4304
  15. Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, Coyle AJ, Liao SM, Maniatis T. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat. Immunol. 4: 491-496 (2003) https://doi.org/10.1038/ni921
  16. Kim SO, Chun KS, Kundu JK, Surh YJ. Inhibitory effects of [6]- gingerol on PMA-induced COX-2 expression and activation of NF-kappaB and p38 MAPK in mouse skin. Biofactors 21: 27-31 (2004) https://doi.org/10.1002/biof.552210107
  17. Youn HS, Saitoh SI, Miyake K, Hwang DH. Inhibition of homodimerization of Toll-like receptor 4 by curcumin. Biochem. Pharmacol. 72: 62-69 (2006) https://doi.org/10.1016/j.bcp.2006.03.022
  18. Youn HS, Lee JY, Fitzgerald KA, Young HA, Akira S, Hwang DH. Specific inhibition of MyD88-independent signaling pathways of TLR3 and TLR4 by resveratrol: Molecular targets are TBK1 and RIP1 in TRIF complex. J. Immunol. 175: 3339-3346 (2005) https://doi.org/10.4049/jimmunol.175.5.3339
  19. Youn HS, Lee JY, Saitoh SI, Miyake K, Kang KW, Choi YJ, Hwang DH. Suppression of MyD88- and TRIF-dependent signaling pathways of Toll-like receptor by (-)-epigallocatechin-3-gallate, a polyphenol component of green tea. Biochem. Pharmacol. 72: 850-859 (2006) https://doi.org/10.1016/j.bcp.2006.06.021
  20. Youn HS, Lee JY, Saitoh SI, Miyake K, Hwang DH. Auranofin, as an anti-rheumatic gold compound, suppresses LPS-induced homodimerization of TLR4. Biochem. Bioph. Res. Co. 350: 866- 871 (2006) https://doi.org/10.1016/j.bbrc.2006.09.097
  21. Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18: 6853-6866 (1999) https://doi.org/10.1038/sj.onc.1203239
  22. Kawai T, Akira S. Signaling to NF-kappaB by Toll-like receptors. Trends Mol. Med. 13: 460-469 (2007) https://doi.org/10.1016/j.molmed.2007.09.002
  23. Karin M, Greten FR. NF-kappaB: Linking inflammation and immunity to cancer development and progression. Nat. Rev. Immunol. 5: 749-759 (2005) https://doi.org/10.1038/nri1703
  24. Li Q, Lu Q, Bottero V, Estepa G, Morrison L, Mercurio F, Verma IM. Enhanced NF-kappaB activation and cellular function in macrophages lacking IkappaB kinase 1 (IKK1). P. Natl. Acad. Sci. USA 102: 12425-12430 (2005) https://doi.org/10.1073/pnas.0505997102
  25. Hayden MS, West AP, Ghosh S. NF-kappaB and the immune response. Oncogene 25: 6758-6780 (2006) https://doi.org/10.1038/sj.onc.1209943
  26. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat. New Biol. 231: 232-235 (1971) https://doi.org/10.1038/newbio231232a0
  27. Kiuchi F, Shibuya M, Sankawa U. Inhibitors of prostaglandin biosynthesis from ginger. Chem. Pharm. Bull. 30: 754-757 (1982) https://doi.org/10.1248/cpb.30.754
  28. Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu. Rev. Pharmacol. Toxicol. 38: 97-120 (1998) https://doi.org/10.1146/annurev.pharmtox.38.1.97
  29. Grzanna R, Lindmark L, Frondoza CG. Ginger--An herbal medicinal product with broad anti-inflammatory actions. J. Med. Food. 8: 125-132 (2005) https://doi.org/10.1089/jmf.2005.8.125
  30. Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK, Lee SS. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: Down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat. Res. 480-481: 243-268 (2001) https://doi.org/10.1016/S0027-5107(01)00183-X
  31. Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nat. Rev. Cancer 3: 768-780 (2003) https://doi.org/10.1038/nrc1189
  32. Khanna D, Sethi G, Ahn KS, Pandey MK, Kunnumakkara AB, Sung B, Aggarwal A, Aggarwal BB. Natural products as a gold mine for arthritis treatment. Curr. Opin. Pharmacol. 7: 344-351 (2007) https://doi.org/10.1016/j.coph.2007.03.002