DOI QR코드

DOI QR Code

Licochalcone E의 항염증 효과와 그 기전에 대한 연구

Anti-Inflammatory Effect of Licochalcone E, a Constituent of Licorice, on Lipopolysaccharide-Induced Inflammatory Responses in Murine Macrophages

  • 박근묵 (대구가톨릭대학교 의생명과학과) ;
  • 전종갑 (한림대학교 화학과) ;
  • 김진경 (대구가톨릭대학교 의생명과학과)
  • Park, Geun-Mook (Department of Biomedical Science, College of Natural Science, Catholic University of Daegu) ;
  • Jun, Jong-Gab (Department of Chemistry and Institute of Natural Medicine, Hallym University) ;
  • Kim, Jin-Kyung (Department of Biomedical Science, College of Natural Science, Catholic University of Daegu)
  • 투고 : 2011.03.03
  • 심사 : 2011.05.16
  • 발행 : 2011.05.30

초록

Licochalcone은 감초의 주요 생리활성 물질로 항균작용, 항암작용 등의 다양한 효과가 있는 것으로 알려져 있다. 최근 감초로부터 licochalcone E가 분리, 동정 되었을 뿐만 아니라, 효과적인 licochalcone E의 합성을 위해 다양한 합성법이 개발되고 있다. 반면, licochalcone E의 생리활성 연구는 매우 미비한 상태이다. 본 연구는 licochclcone E의 항염증 활성과 그 기전의 일단을 밝히는 것을 목적으로 진행 되었다. 생쥐의 대식세포주인 RAW264.7 세포에 lipopolysaccharide (LPS)를 처리 염증반응을 유도하고, licochalcone E를 처리한 한 결과, licochalconeE는 LPS 처리에 의한 nitric oxide (NO), prostaglandin $E_2$ ($PGE_2$) 및 염증성 사이토카인의 분비를 현저히 억제시키는 것을 관찰 할 수 있었으며, NO와 $PGE_2$ 생합성효소인 iNOS와 COX-2 단백질의 발현 또한 억제시킴을 확인할 수 있었다. 이러한 licochalcone E의 항염증 활성의 기전을 밝히기 위해 염증반응에 핵심적인 역할을 하는 전사인자인 nuclear factor-${\kappa}$B (NF-${\kappa}$B)의 활성을 관찰한 결과, licochalcone E의 처리가 NF-${\kappa}$B의 DNA결합을 억제하는 것을 확인 하였다. 이러한 연구결과로 볼 때 licochalcone E가 NF-${\kappa}$B의 활성을 억제하여, 염증반응의 매개물질인 NO, $PGE_2$, 염증성 사이토카인 등의 생성을 억제함으로 항염증활성을 나타내는 것으로 판단된다.

Licochalcone, a major phenolic constituent of the licorice species Glycyrrhiza inflata, a constituent of licorice, exhibits various biological properties, including chemopreventive-, antibacterial-, and anti-spasmodic activities. Recently, Licochalcone E (LicE) was isolated from the roots of Glycyrrhiza inflate, however its biological functions have not been fully examined. In the present study, we investigated the ability of LicE to regulate inflammation reactions in macrophages. Our in vitro experiments using murine macrophages, RAW264.7 cells, showed that LicE suppressed not only nitric oxide (NO) and prostaglandin $E_2$ generation, but also the expression of inducible NO synthase and cyclooxygenase-2 induced by lipopolysaccharide (LPS). Similarly, LicE inhibited the release of proinflammatory cytokines induced by LPS in RAW264.7 cells, including tumor necrosis factor-${\alpha}$ and interleukin-6. The underlying mechanism of LicE on anti-inflammatory action correlated with down-regulation of the nuclear factor-${\kappa}$B. Our data collectively indicate that LicE inhibited the production of several inflammatory mediators and might be used in the treatment of various inflammatory diseases.

키워드

참고문헌

  1. Aktan, F. 2004. iNOS-mediated nitric oxide production and its regulation. Life Sci. 75, 639-653. https://doi.org/10.1016/j.lfs.2003.10.042
  2. Baker, R. G., M. S. Hayden, and S. Ghosh. 2011. NF-$\kappa$B, inflammation, and metabolic disease. Cell Metab. 13, 11-22. https://doi.org/10.1016/j.cmet.2010.12.008
  3. Barfod, L., K. Kemp, M. Hansen, and A. Kharazmi. 2002. Chalcones from chinese liquorice inhibit proliferation of T cells and production of cytokines. Int. Immunopharmacol. 2, 545-555. https://doi.org/10.1016/S1567-5769(01)00202-8
  4. Bielory, L. 2004. Complementary and alternative interventions in asthma, allergy, and immunology. Ann. Allergy Asthma Immunol. 93, S45-54. https://doi.org/10.1016/S1081-1206(10)61486-X
  5. Blackwell, T. S. and J. W. Christman. 1997. The role of nuclear factor-kappa B in cytokine gene regulation. Am. J. Respir. Cell Mol. Biol. 7, 3-9.
  6. Carbonell-Barrachina, A. A., P. Aracil, E. Garcia, F. Burlo, and F. Martinez-Sanchez. 2003. Source of arsenic in licorice confectionery products. J. Agric. Food Chem. 51, 1749-1752. https://doi.org/10.1021/jf026057h
  7. Chang, H. J., G. Yoon, J. S. Park, M. H. Kim, M. K. Baek, N. H. Kim, B. A. Shin, B. W. Ahn, S. H. Cheon, and Y. D. Jung. 2007. Induction of apoptosis by the licochalcone E in endothelial cells via modulation of NF-kappaB and Bcl-2 Family. Biol. Pharm. Bull. 30, 2290-2293. https://doi.org/10.1248/bpb.30.2290
  8. Cho, M. K., S. H. Suh, and S. G. Kim. 2002. JunB/AP-1 and NF-kappa B-mediated induction of nitric oxide synthase by bovine type I collagen in serum-stimulated murine macrophages. Nitric Oxide 6, 319-332. https://doi.org/10.1006/niox.2001.0415
  9. Cho, Y. C., S. H. Lee, G. Yoon, H. S. Kim, J. Y. Na, H. J. Choi, C. W. Cho, S. H. Cheon, and B. Y. Kang. 2010. Licochalcone E reduces chronic allergic contact dermatitis and inhibits IL-12p40 production through down-regulation of NF-kappa B. Int. Immunopharmacol. 10, 1119-26. https://doi.org/10.1016/j.intimp.2010.06.015
  10. Fu, Y. T., C. Hsieh, J. Guo, J. Kunicki, M. Y. Lee, Z. Darzynkiewicz, and J. M. Wu. 2004. Licochalcone-A, a novel flavonoid isolated from licorice root (Glycyrrhiza glabra), causes G2 and late-G1 arrests in androgen-independent PC-3 prostate cancer cells. Biochem. Biophys. Res. Commun.322, 263-270. https://doi.org/10.1016/j.bbrc.2004.07.094
  11. Fukai, T., A. Marumo, K. Kaitou, T. Kanda, S. Terada, and T. Nomura. 2002. Anti-Helicobacter pylori flavonoids from licorice extract. Life Sci. 71, 1449-1463. https://doi.org/10.1016/S0024-3205(02)01864-7
  12. Fukai, T., K. Satoh, T. Nomura, and H. Sakagami. 2003. Preliminary evaluation of antinephritis and radical scavenging activities of glabridin from Glycyrrhiza inflate. Fitoterapia 74, 624-629. https://doi.org/10.1016/S0367-326X(03)00164-3
  13. Ghezzi, P. and A. Cerami. 2005. Tumor necrosis factor as a pharmacological target. Mol. Biotechnol. 31, 239-244. https://doi.org/10.1385/MB:31:3:239
  14. Guha, M. and N. Mackman. 2001. LPS induction of gene expression in human monocytes. Cell Signal. 13, 85-94. https://doi.org/10.1016/S0898-6568(00)00149-2
  15. Gyrd-Hansen, M. and P. Meier. 2010. IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer. Nat. Rev. Cancer 10, 561-74. https://doi.org/10.1038/nrc2889
  16. Haraguchi, H., H. Ishikawa, K. Mizutani, Y. Tamura, and T. Kinoshita. 1998. Antioxidative and superoxide scavenging activities of retrochalcones in Glycyrrhiza inflata. Bioorg. Med. Chem. 6, 339-347. https://doi.org/10.1016/S0968-0896(97)10034-7
  17. Jachak, S. M. and A. Saklani. 2007. Challenges and opportunities in drug discovery from plant. Curr. Sci. 92, 1251-1257.
  18. Jeon, J. H., M. R. Kim, E. M. Kwon, N. R. Lee, and J. G. Jun. 2011. Highly efficient synthesis of licochalcone E through water-accelerated [3,3]-sigmatropic rearrangement of allyl aryl ether. Bull. Korean Chem. Soc. 32, 1059-1062. https://doi.org/10.5012/bkcs.2011.32.3.1059
  19. Kamimura, D., K. Ishihara, and T. Hirano. 2003. IL-6 signal transduction and its physiological roles: the signal orchestration model. Rev. Physiol. Biochem. Pharmacol. 149, 1-38.
  20. Kim, J. K., S. M. Oh, H. S. Kwon, Y. S. Oh, S. S. Lim, and H. K. Shin. 2006. Anti-inflammatory effect of roasted licorice extracts on lipopolysaccharide-induced inflammatory responses in murine macrophages. Biochem. Biophys. Res. Commun. 345, 1215-1223. https://doi.org/10.1016/j.bbrc.2006.05.035
  21. Kwon, H. S., S. M. Oh, and J. K. Kim. 2008. Glabridin, a functional compound of liquorice, attenuates colonic inflammation in mice with dextran sulphate sodium-induced colitis. Clin. Exp. Immunol. 151, 165-173.
  22. Lang, R. M., M. Hammer, and J. Mages. 2006. DUSP meet immunology: dual specificity MAPK phosphatases in control of the inflammatory response. J. Immunol. 177, 7497-7504. https://doi.org/10.4049/jimmunol.177.11.7497
  23. Lawrence, T. D., A. Willoughby, and D. W. Gilroy. 2002. Anti-inflammatory lipid mediators and insights into the resolution of inflammation. Nat. Rev. Immunol. 2, 787-795. https://doi.org/10.1038/nri915
  24. Lo, C. J., M. Fu, F. R. Lo, and H. G. Cryer. 2000. Cyclooxygenase 2 (COX-2) gene activation is regulated by cyclic adenosine monophosphate. Shock 13, 41-45. https://doi.org/10.1097/00024382-200013010-00008
  25. Montecucco, F. and F. Mach. 2009. Common inflammatory mediators orchestrate pathophysiological processes in rheumatoid arthritis and atherosclerosis. Rheumatology 48, 11-22. https://doi.org/10.1093/rheumatology/kep705
  26. Muller, J. M., H. W. Ziegler-Heitbrock, and P. A. Baeuerle. 1993. Nuclear factor kappa B, a mediator of lipopolysaccharide effects. Immunobiology 187, 233-56. https://doi.org/10.1016/S0171-2985(11)80342-6
  27. Nielsen, S. F., T. Boesen, M. Larsen, K. Schonning, and H. Kromann. 2004. Antibacterial chalcones-bioisosteric replacement of the 4′-hydroxy group. Bioorg. Med. Chem. 12, 3047-3054. https://doi.org/10.1016/j.bmc.2004.03.071
  28. Ohsawa, M., T. Koyama, N. Nara, and S. Hirosawa. 2003. Induction of tissue factor expression in human monocytic cells by protease inhibitors through activating activator protein- 1 (AP-1) with phosphorylation of Jun-N-terminal kinase and p38. Throm. Res. 112, 313-320. https://doi.org/10.1016/j.thromres.2003.12.018
  29. O'Shea, J. J. and P. J. Murray. 2008. Cytokine signaling modules in inflammatory responses. Immunity 28, 477-487. https://doi.org/10.1016/j.immuni.2008.03.002
  30. Renard, P. and M. Raes. 1999. The proinflammatory transcription factor NFkappaB: a potential target for novel therapeutical strategies. Cell Biol. Toxicol. 15, 341-3444. https://doi.org/10.1023/A:1007652414175
  31. Tominaga, K., S. Saito, M. Matsuura, and M. Nakano. 1999. Lipopolysaccharide tolerance in murine peritoneal macrophages induces downregulation of the lipopolysaccharide signal transduction pathway through mitogen-activated protein kinase and nuclear factor-kappaB cascades, but not lipopolysaccharide-incorporation steps. Biochim. Biophys. Acta. 1450, 130-144. https://doi.org/10.1016/S0167-4889(99)00037-3
  32. Yamamoto, Y. and R. B. Gaynor. 2001. Role of the NF-kappaB pathway in the pathogenesis of human disease states. Curr. Mol. Med. 1, 287-296. https://doi.org/10.2174/1566524013363816
  33. Yoon, G., Y. D. Jung, and S. H. Cheon. 2005. Cytotoxic allyl retrochalcone from the roots of Glycyrrhiza inflata. Chem. Pharm. Bull. 53, 694-695. https://doi.org/10.1248/cpb.53.694
  34. Zhou, S., H. L. Koh, Y. Gao, Z. Y. Gong, and E. J. Lee. 2004. Herbal bioactivation: the good, the bad and the ugly. Life Sci. 74, 935-968. https://doi.org/10.1016/j.lfs.2003.09.035
  35. Ziegler, H. L., H. S. Hansen, D. Staerk, S. B. Christensen, H. Hagerstrand, and J. W. Jaroszewski. 2004. The antiparasitic compound licochalcone A is a potent echinocytogenic agent that modifies the erythrocyte membrane in the concentration range where antiplasmodial activity is observed. Antimicrob. Agents. Chemother. 48, 4067-4071. https://doi.org/10.1128/AAC.48.10.4067-4071.2004

피인용 문헌

  1. Mechanisms by Which Licochalcone E Exhibits Potent Anti-Inflammatory Properties: Studies with Phorbol Ester-Treated Mouse Skin and Lipopolysaccharide-Stimulated Murine Macrophages vol.14, pp.6, 2013, https://doi.org/10.3390/ijms140610926
  2. Antimicrobial and Anti-inflammatory Activities of Extracts from Glycyrrhizae radix cultured with Paecilomyces japonica vol.26, pp.3, 2016, https://doi.org/10.17495/easdl.2016.6.26.3.215