Korean Journal of Plant Resources (한국자원식물학회지)

The Plant Resources Society of Korea (한국자원식물학회)
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Study on the Immunomodulatory Effects of Ellagic Acid and their Mechanisms Related to Toll-like Receptor 4 in Macrophages

Ellagic acid가 대식세포의 면역조절작용에 미치는 영향과 Toll-like receptor 4 관련 작용기전 연구

  • NamKoong, Seung (Department of Physical Therapy, Kangwon National University) ;
  • Kim, Ye-Jin (Department of Herbal Medicine Resource, Kangwon National University) ;
  • Kim, Taeseong (Department of Herbal Medicine Resource, Kangwon National University) ;
  • Sohn, Eun-Hwa (Department of Herbal Medicine Resource, Kangwon National University)
  • 남궁승 (강원대학교 물리치료학과) ;
  • 김예진 (강원대학교 생약자원개발학과) ;
  • 김태성 (강원대학교 생약자원개발학과) ;
  • 손은화 (강원대학교 생약자원개발학과)
  • Received : 2012.05.03
  • Accepted : 2012.10.09
  • Published : 2012.10.29
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Abstract

Ellagic acid (EA) is a phenolic compound in fruits and nuts including raspberries, strawberries, grapes and walnuts. Previous studies have indicated that EA possesses antioxidant activity, growth-inhibition and apoptosis-promoting activity in cancer cells. However, macrophage mediated cytotoxicity and immunomodulating effects on cancer cells have not been clarified. In the present study, we show that EA increased effects on macrophage mediated tumoricidal activity and NO production without direct tumor cell cytotoxicity. To further determine whether TLR4 (toll like receptor 4) is involved in anti-tumor activity, cells were treated TLR4 signaling inhibitor, CLI-095 in the presence of EA. CLI-095 treatment partially reduced macrophage-mediated tumoridial activity. EA also has inhibitory effects of NO production induced by LPS, whereas phagocytic activity was not changed. These results suggest that EA induces macrophage mediated tumoricidal activity which is partially related to TLR4 signaling and has a potential adjuvant in cancer therapy.

본 연구는 EA에 의한 대식세포의 활성화를 매개로 한 항암효과와 항암작용과 관련된 대식세포의 면역조절효과를 확인하였다. 연구 결과 EA에 의해 RAW264.7세포 및 peritoneal macrophage 모두에서 항암효과가 증가하였으며, 증가된 대식세포의 항암효과는 TLR4 signaling을 blocking하는 CLI-095을 함께 처리하였을 때 일부 감소되었다. 이는 EA에 의한 항암 효과가 부분적으로 TLR4를 경유하는 기전으로 나타나는 것을 의미한다. 또한, EA에 대한 대식세포의 NO 분비조절효과를 측정하였으며, EA는 대식세포의 NO 생성을 증가시켰으나, 인위적으로 염증을 유발시켜 NO를 과도하게 분비한 상태에서는 NO 분비를 오히려 억제시키는 결과를 나타내었다. 이와 같이 EA에 의한 NO조절에 대한 이중 효과는 인체에 면역증강과 항염증 효과라는 긍정적인 효과를 나타내는 방향으로 조절하고 있으므로 EA를 이용한 항암요법의 보조제 및 면역보조제로써의 활용에 유익할 것으로 사료된다. 향후 EA에 대한 항암 작용 및 NO 조절에서 세포내 신호전달 작용기전에 대한 심도 있는 연구가 진행되어야 할 것으로 보인다.

Keywords

References

  1. Adams, D.O. and T.A. Hamilton. 1984. The cell biology of macrophage activation. Annu. Rew. Immunol. 2:283-318. https://doi.org/10.1146/annurev.iy.02.040184.001435
  2. Akira, S. 2003. Toll-like receptor signaling. J. Biol. Chem. 278:38105-38108. https://doi.org/10.1074/jbc.R300028200
  3. Chen, R., A.B. Alvero, D.A. Silasi, K.D. Steffensen and G. Mor. 2008. Cancers take their toll-the function and regulation of toll-like receptors in cancer cells. Oncogene 27:225-233. https://doi.org/10.1038/sj.onc.1210907
  4. Choung, M.G. and E.H. Sohn. 2011. Anti-tumor activity of saponin fraction of Platycodon gradiflourm through immunomodulatory effects associated with NO production in RAW264.7 cells. J. Korean Plant Res. 24(5):557-563 (in Korean). https://doi.org/10.7732/kjpr.2011.24.5.557
  5. Daniel, E.M., A.S. Kropnick, Y.H. Heur, J.A. Blinzler, R.W. Nims and G.D. Stoner. 1989. Extraction, stability and quantitation of ellagic acid in various fruits and nuts. J. Food Compos. Anal. 2:338-349. https://doi.org/10.1016/0889-1575(89)90005-7
  6. Do, H., N.S. Kang, S. Pyo, T.R. Billiar and E.H. Sohn. 2010. Differential regulation by fucoidan of IFN-$\gamma$-induced NO production in glial cells and macrophages. J. Cell Biochem. 111:1337-1345. https://doi.org/10.1002/jcb.22860
  7. Edderkaoui, M., I. Odinokova, I. Ohno, I. Gukovsky, V.L. Go, S.J. Pandol and A.S. Gukovskaya. 2008. Ellagic acid induces apoptosis through inhibition of nuclear factor $\kappa B$ in pancreatic cancer cells. World J. Gastroenterol. 14:3672-3680. https://doi.org/10.3748/wjg.14.3672
  8. Gonzalez-Sarrias, A., J.C. Espin, F.A. Tomas-Barberan and M.T. Garcia-Conesa. 2009. Gene expression, cell cycle arrest and MAPK signalling regulation in Caco-2 cells exposed to ellagic acid and its metabolites, urolithins. Mol. Nutr. Food Res. 53:686-698. https://doi.org/10.1002/mnfr.200800150
  9. Hamsa, T.P. and G. Kuttan. 2011. Evaluation of the antiinflammatory and anti-tumor effect of ipomoea obscura (L) and its mode of action through the inhibition of proinflammatory cytokines, nitric oxide and COX-2. Inflammation 34:171-183. https://doi.org/10.1007/s10753-010-9221-4
  10. Jimenez, F., T.F. Mitts, K. Liu, Y. Wang and A. Hinek. 2006. Ellagic and tannic acids protect newly synthesized elastic fibers from premature enzymatic degradation in dermal fibroblast cultures. J. Invest. Dermatol. 126:1272-1280. https://doi.org/10.1038/sj.jid.5700285
  11. Jofre-Monseny, L., S. de Pascual-Teresa, E. Plonka, P. Huebbe, C. Boesch- Saadatmandi, A.M. Minihane and G. Rimbach. 2007. Differential effects of apolipoprotein E3 and E4 on markers of oxidative status in macrophages. Br. J. Nutr. 97:864-871. https://doi.org/10.1017/S0007114507669219
  12. Kang, N.S. and E.H. Sohn. 2010. Immunomodulatory effects of fructus and semen from Rosa rugosa on macrophages. J. Korean Plant Res. 23(5):399-405 (in Korean).
  13. Kawasaki, K., S. Akashi, R. Shimazu, T. Yoshida, K. Miyake and M. Nishijima. 2000. Mouse toll-like receptor 4-MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol. J. Biol. Chem. 275:2251-2254. https://doi.org/10.1074/jbc.275.4.2251
  14. Kelly, M.G., A.B. Alvero, R. Chen, D.A. Silasi, V.M. Abrahams, S. Chan, I. Visintin, T. Rutherford and G. Mor. 2006. TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res. 66:3859-3868. https://doi.org/10.1158/0008-5472.CAN-05-3948
  15. Kwon, S., R.L. Newcomb and S.C. George. 2001. Mechanisms of synergistic cytokine-induced nitric oxide production in human alveolar epithelial cells. Nitric Oxide 5:534-546. https://doi.org/10.1006/niox.2001.0387
  16. Larrosa, M., F.A. Tomas-Barberan and J.C. Espin. 2006. The dietary hydrolysable tannin punicalagin releases ellagic acid that induces apoptosis in human colon adenocarcinoma Caco-2 cells by using the mitochondrial pathway. J. Nutr. Biochem. 17:611-625. https://doi.org/10.1016/j.jnutbio.2005.09.004
  17. Li, T.M., G.W. Chen, C.C. Su, J.G. Lin, C.C. Yeh, K.C. Cheng and J.G. Chung. 2005. Ellagic acid induced p53/p21 expression, G1 arrest and apoptosis in human bladder cancer T24 cells. Anticancer Res. 25:971-979.
  18. Malrletta, M.A., Z. Chen and K.M. Rusche. 1998. Catalysis by nitric oxide systhase. Curr. Opin. Chem. Biol. 2:656-663. https://doi.org/10.1016/S1367-5931(98)80098-7
  19. Mertens-Talcott, S.U., J.A. Bomser, C. Romero, S.T. Talcott and S.S. Percival. 2005. Ellagic acid potentiates the effect of quercetin on p21waf1/cip1, p53, and MAP-kinases without affecting intracellular generation of reactive oxygen species in vitro. J. Nutr. 135:609-614.
  20. Mukhtar, H., M. Das, W.A. Khan, Z.Y. Wang, D.P. Bik and D.R. Bickers. 1988. Exceptional activity of tannic acid among naturally occurring plant phenols in protecting against 7,12- dimethylbenz(a)anthracene-, benzo(a)pyrene-, 3-methylcholanthrene-, and N-methyl-Nnitrosourea-induced skin tumorigenesis in mice. Cancer Res. 48:2361-2365.
  21. Osawa, T., A. Ide, J.D. Su and M, Namiki. 1987. Inhibition of lipid peroxidation by ellagic acid. J. Agric. Food Chem. 35:808-812. https://doi.org/10.1021/jf00077a042
  22. Pacheco-Palencia, L.A., G. Noratto, L. Hingorani, S.T. Talcott and S.U. Mertens-Talcott. 2008. Protective effects of standardized pomegranate (Punica granatum L.) polyphenolic extract in ultraviolet-irradiated human skin fibroblasts. J. Agric. Food Chem. 56:8434-8441. https://doi.org/10.1021/jf8005307
  23. Shen, B., M. Hagiwara, Y.Y. Yao, L. Chao and J. Chao. 2008. Salutary effect of kallistatin in saltinduced renal injury, inflammation, and fibrosis via antioxidative stress. Hypertension 51:1358-1365. https://doi.org/10.1161/HYPERTENSIONAHA.107.108514
  24. Shi, Z., Z. Cai, A. Sanchez, T. Zhang, S. Wen, J. Wang, J. Yang, S. Fu and D. Zhang. 2011. A novel toll-like receptor that recognizes vesicular stomatitis virus. J. Biol. Chem. 286: 4517-4524. https://doi.org/10.1074/jbc.M110.159590
  25. Stoner, G.D. and A. Gupta. 2001. Etiology and chemoprevention of esophageal squamous cell carcinoma. Carcinogenesis 22:1737-1746. https://doi.org/10.1093/carcin/22.11.1737
  26. Thresiamma, K.C. and R. Kuttan. 1996. Inhibition of liver fibrosis by ellagic acid. Indian J. Physiol. Pharmacol. 40: 363-366.
  27. USDA Economic Research Service. 1988. Fruits and tree nuts: Situation and outlook yearbook, U.S. Department of Agriculture, Hyattsville, M.D.
  28. Won, J.S., Y.B. Im, A.K. Singh and I. Singh. 2004. Dual role of cAMP in iNOS expression in glial cells and macrophages is mediated by differential regulation of p38-MAPK/ATF-2 activation and iNOS stability. Free Radic. Biol. Med. 37: 1834-1844. https://doi.org/10.1016/j.freeradbiomed.2004.08.017
  29. Zhang, L., H. Zhu, Y. Lun, D. Yan, L. Yu, B. Du and X. Zhu. 2007. Proteomic analysis of macrophages: a potential way to identify novel proteins associated with activation of macrophages for tumor cell killing. Cell. Mol. Immunol. 4:359-367.

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