Korean Journal of Food Science and Technology (한국식품과학회지)

Korean Society of Food Science and Technology (한국식품과학회)
권호 표지

NF-${\kappa}$ B Activation and Cyclooxygenase-2 Expression Induced by Toll-Like Receptor Agonists can be Suppressed by Isoliquiritigenin

Isoliquiritigenin의 toll-like receptor agonists에 의해서 유도된 NF-${\kappa}$B 활성화와 cyclooxygenase-2 발현 억제

  • Park, Se-Jeong (Department of Medical Science, College of Medical Sciences, Soonchunhyang University) ;
  • Yang, Seung-Ju (Department of Biomedical Laboratory Science, Konyang University) ;
  • Youn, Hyung-Sun (Department of Medical Science, College of Medical Sciences, Soonchunhyang University)
  • 박세정 (순천향대학교 의료과학대학 의료과학과) ;
  • 양승주 (건양대학교 임상병리학과) ;
  • 윤형선 (순천향대학교 의료과학대학 의료과학과)
  • Published : 2009.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

Toll-like receptors(TLRs) are pattern recognition receptors(PRRs) that recognize pathogen-associated molecular patterns(PAMPs) and regulate the activation of innate immunity. All TLR signaling pathways culminate in the activation of NF-${\kappa}$B, leading to the induction of inflammatory gene products such as COX-2. Licorice (Glycyrrhiza uralensis) has been used for centuries as an herbal medicine. Isoliquiritigenin(ILG), a simple chalcone-type flavonoid, is an active component present in licorice and has been used to treat many chronic diseases. However, the mechanism as to how ILG mediates health effects is still largely unknown. In the present report, we present biochemical evidence that ILG inhibits the NF-${\kappa}$B activation induced by TLR agonists and the overexpression of downstream signaling components of TLRs, MyD88, IKK${\beta}$, and p65. ILG also inhibits TLR agonists-induced COX-2 expression. These results suggest that anti-inflammatory effects of ILG are caused by modulation of the immune responses regulated by TLR signaling pathways.

선천성 면역 반응을 위해 중요한 역할을 하는 TLRs가 외부 병원성 물질에 자극을 받게 되면 NF-${\kappa}$B를 활성화시키며, 그 결과로 염증을 유도하는 COX와 같은 유전자를 발현한다. 이번 연구에서, 옛날부터 지금까지 전통적인 약재로써 질병 치료에 다양하게 쓰이고 있는 감초의 뿌리에서 추출한 성분 중의 하나인 ILG가 NF-${\kappa}$B활성과 COX 발현을 어떻게 조절하여 항염증 효과를 가지고 있는지 알아보았다. ILG는 TLR agonists인 MALP-2, Poly[I:C], 그리고 LPS에 의해 유도된 NF-${\kappa}$B 활성화와 COX-2 발현을 억제시켰다. 또한 ILG는 리간드(ligand)에 독립적인 TLRs signaling downstream molecules인 MyD88, IKK ${\beta}$, 그리고 p65에 의해서 유도된 NF-${\kappa}$B 활성을 억제시켰다. 이러한 결과는 한약재로서 많이 이용되는 감초가 단지 한약의 쓴맛을 줄이기 위함이 아니라 TLRs 신호전달 체계를 조절하여 항염증 효과를 가지고 있다는 것을 보여주는 것이라 할 수 있겠다.

Keywords

References

  1. Fintelmann V. Modern phytotherapy and its uses in gastrointestinal conditions. Planta Med. 57: S48-S52 (1991) https://doi.org/10.1055/s-2006-960229
  2. Kim JY, Park SJ, Yun KJ, Cho YW, Park HJ, Lee KT. Isoliquiritigenin isolated from the roots of Glycyrrhiza uralensis inhibits LPS-induced iNOS and COX-2 expression via the attenuation of NF-kappaB in RAW 264.7 macrophages. Eur. J. Pharmacol. 584:175-184 (2008) https://doi.org/10.1016/j.ejphar.2008.01.032
  3. Kamei J, Saitoh A, Asano T, Nakamura R, Ichiki H, Iiduka A, Kubo M. Pharmacokinetic and pharmacodynamic profiles of the antitussive principles of Glycyrrhizae radix (licorice), a main component of the Kampo preparation Bakumondo-to (Mai-mendong-tang). Eur. J. Pharmacol. 507: 163-168 (2005) https://doi.org/10.1016/j.ejphar.2004.11.042
  4. Haggag EG, Abou-Moustafa MA, Boucher W, Theoharides TC. The effect of a herbal water-extract on histamine release from mast cells and on allergic asthma. J. Herb. Pharmacother. 3: 41-54(2003) https://doi.org/10.1300/J157v03n04_03
  5. Fukai T, Satoh K, Nomura T, Sakagami H. Preliminary evaluation of antinephritis and radical scavenging activities of glabridin from Glycyrrhiza glabra. Fitoterapia 74: 624-629 (2003) https://doi.org/10.1016/S0367-326X(03)00164-3
  6. Yokota T, Nishio H, Kubota Y, Mizoguchi M. The inhibitory effect of glabridin from licorice extracts on melanogenesis and inflammation. Pigm. Cell Res. 11: 355-361 (1998) https://doi.org/10.1111/j.1600-0749.1998.tb00494.x
  7. Zhou S, Koh HL, Gao Y, Gong ZY, Lee EJ. Herbal bioactivation: the good, the bad and the ugly. Life Sci. 74: 935-968 (2004) https://doi.org/10.1016/j.lfs.2003.09.035
  8. Yu SM, Kuo SC. Vasorelaxant effect of isoliquiritigenin, a novel soluble guanylate cyclase activator, in rat aorta. Brt. J. Pharmacol.114: 1587-1594 (1995) https://doi.org/10.1111/j.1476-5381.1995.tb14943.x
  9. Tawata M, Aida K, Noguchi T, Ozaki Y, Kume S, Sasaki H, Chin M, Onaya T. Anti-platelet action of isoliquiritigenin, an aldose reductase inhibitor in licorice. Eur. J. Pharmacol. 212: 87-92 (1992) https://doi.org/10.1016/0014-2999(92)90076-G
  10. Kakegawa H, Matsumoto H, Satoh T. Inhibitory effects of some natural products on the activation of hyaluronidase and their antiallergic actions. Chem. Pharm. Bull. 40: 1439-1442 (1992) https://doi.org/10.1248/cpb.40.1439
  11. Takeda K, Akira S. Toll-like receptors in innate immunity. Int. Immunol. 17: 1-14 (2005)
  12. Medzhitov R. Toll-like receptors and innate immunity. Nat. Rev. Immunol. 1: 135-145 (2001) https://doi.org/10.1038/35100529
  13. 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
  14. 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
  15. Kawai T, Akira S. Toll-like receptor and RIG-I-like receptor signaling. Ann. NY Acad. Sci. 1143: 1-20 (2008) https://doi.org/10.1196/annals.1443.020
  16. Harris RE, Beebe-Donk J, Doss H, Burr Doss D. Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: A critical review of non-selective COX-2 blockade (review). Oncol. Rep. 13: 559-583 (2005)
  17. Naesdal J, Brown K. NSAID-associated adverse effects and acid control aids to prevent them: A review of current treatment options. Drug Safety 29: 119-132 (2006) https://doi.org/10.2165/00002018-200629020-00002
  18. Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nat. Rev. Cancer 3: 768-780 (2003) https://doi.org/10.1038/nrc1189
  19. 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
  20. 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)
  21. 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
  22. 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
  23. Dinkova-Kostova AT, Massiah MA, Bozak RE, Hicks RJ, Talalay P. Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups. P. Natl. Acad. Sci. USA 98: 3404-3409(2001) https://doi.org/10.1073/pnas.051632198
  24. Siedle B, Garcia-Pineres AJ, Murillo R, Schulte-Monting J, Castro V, Rungeler P, Klaas CA, Da Costa FB, Kisiel W, Merfort I. Quantitative structure-activity relationship of sesquiterpene lactones as inhibitors of the transcription factor NF-kappaB. J. Med. Chem. 47: 6042-6054 (2004) https://doi.org/10.1021/jm049937r
  25. Na HK, Surh YJ. Transcriptional regulation via cysteine thiol modification: a novel molecular strategy for chemoprevention and cytoprotection. Mol. Carcinogen. 45: 368-380 (2006) https://doi.org/10.1002/mc.20225
  26. Rungeler P, Castro V, Mora G, Goren N, Vichnewski W, Pahl HL, Merfort I, Schmidt TJ. Inhibition of transcription factor NFkappaB by sesquiterpene lactones: A proposed molecular mechanism of action. Bioorg. Med. Chem. 7: 2343-2352 (1999) https://doi.org/10.1016/S0968-0896(99)00195-9
  27. Garcia-Pineres AJ, Castro V, Mora G, Schmidt TJ, Strunck E, Pahl HL, Merfort I. Cysteine 38 in p65/NF-kappaB plays a crucial role in DNA binding inhibition by sesquiterpene lactones. J. Biol. Chem. 276: 39713-39720 (2001) https://doi.org/10.1074/jbc.M101985200
  28. Youn HS, Lee JK, Choi YJ, Saitoh SI, Miyake K, Hwang DH, Lee JY. Cinnamaldehyde suppresses toll-like receptor 4 activation mediated through the inhibition of receptor oligomerization. Biochem.Pharmacol. 75: 494-502 (2008) https://doi.org/10.1016/j.bcp.2007.08.033
  29. Kumar S, Sharma A, Madan B, Singhal V, Ghosh B. Isoliquiritigenin inhibits IkappaB kinase activity and ROS generation to block TNF-alpha induced expression of cell adhesion molecules on human endothelial cells. Biochem. Pharmacol. 73: 1602-1612(2007) https://doi.org/10.1016/j.bcp.2007.01.015
  30. 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-kappaB activation. Nat. Immunol. 5: 503-507 (2004) https://doi.org/10.1038/ni1061