Browse > Article
http://dx.doi.org/10.1007/s10059-009-0026-y

Inhibition of Homodimerization of Toll-like Receptor 4 by 6-Shogaol  

Ahn, Sang-Il (Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University)
Lee, Jun-Kyung (Cell Culture Process Research and Development Center, Celltrion Inc.)
Youn, Hyung-Sun (Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University)
Abstract
Toll-like receptors (TLRs) play a critical role in sensing microbial components and inducing innate immune and inflammatory responses by recognizing invading microbial pathogens. Lipopolysaccharide-induced dimerization of TLR4 is required for the activation of downstream signaling pathways including nuclear factor-kappa B ($NF-{\kappa}B$). Therefore, TLR4 dimerization may be an early regulatory event in activating ligand-induced signaling pathways and induction of subsequent immune responses. Here, we report biochemical evidence that 6-shogaol, the most bioactive component of ginger, inhibits lipopolysaccharide-induced dimerization of TLR4 resulting in the inhibition of $NF-{\kappa}B$ activation and the expression of cyclooxygenase-2. Furthermore, we demonstrate that 6-shogaol can directly inhibit TLR-mediated signaling pathways at the receptor level. These results suggest that 6-shogaol can modulate TLR-mediated inflammatory responses, which may influence the risk of chronic inflammatory diseases.
Keywords
cyclooxygenase-2; dimerization; lipopolysaccharide; $NF-{\kappa}B$; toll like receptors;
Citations & Related Records
Times Cited By KSCI : 4  (Citation Analysis)
Times Cited By Web Of Science : 17  (Related Records In Web of Science)
연도 인용수 순위
1 Afzal, M., Al-Hadidi, D., Menon, M., Pesek, J., and Dhami, M.S. (2001). Ginger: an ethnomedical, chemical and pharmacological review. Drug Metabol. Drug Interact. 18, 159-190
2 Doyle, S.L., and O'Neill, L.A. (2006). Toll-like receptors: from the discovery of NFkappaB to new insights into transcriptional regulations in innate immunity. Biochem. Pharmacol. 72, 1102-1113   DOI   ScienceOn
3 Medzhitov, R., Preston-Hurlburt, P., and Janeway, C.A., Jr. (1997). A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394-397   DOI   ScienceOn
4 Pan, M.H., Hsieh, M.C., Hsu, P.C., Ho, S.Y., Lai, C.S., Wu, H., Sang, S., and Ho, C.T. (2008). 6-Shogaol suppressed lipopolysaccharide-induced up-expression of iNOS and COX-2 in murine macrophages. Mol. Nutr. Food Res. 52, 1-11
5 Sato, S., Sugiyama, M., Yamamoto, M., Watanabe, Y., Kawai, T., Takeda, K., and Akira, S. (2003). Toll/IL-1 receptor domaincontaining 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   DOI
6 Youn, H.S., Lee, J.Y., Fitzgerald, K.A., Young, H.A., Akira, S., and Hwang, D.H. (2005). 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   DOI
7 Takeuchi, O., Sato, S., Horiuchi, T., Hoshino, K., Takeda, K., Dong, Z., Modlin, R.L., and Akira, S. (2002). Cutting edge: role of Tolllike receptor 1 in mediating immune response to microbial lipoproteins. J. Immunol. 169, 10-14   DOI
8 Youn, H.S., Saitoh, S.I., Miyake, K., and Hwang, D.H. (2006b). Inhibition of homodimerization of Toll-like receptor 4 by curcumin. Biochem. Pharmacol. 72, 62-69   DOI   ScienceOn
9 Tao, X., Xu, Y., Zheng, Y., Beg, A.A., and Tong, L. (2002). An extensively associated dimer in the structure of the C713S mutant of the TIR domain of human TLR2. Biochem. Biophys. Res. Commun. 299, 216-221   DOI   ScienceOn
10 Takeuchi, O., Kawai, T., Muhlradt, P.F., Morr, M., Radolf, J.D., Zychlinsky, A., Takeda, K., and Akira, S. (2001). Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int. Immunol. 13, 933-940   DOI   ScienceOn
11 Youn, H.S., Lim, H.J., Choi, Y.J., Lee, J.Y., Lee, M.Y., and Ryu, J.H. (2008a). Selenium suppresses the activation of transcription factor NF-kappa B and IRF3 induced by TLR3 or TLR4 agonists. Int. Immunopharmacol. 8, 495-501   DOI   ScienceOn
12 Takeda, K., and Akira, S. (2005). Toll-like receptors in innate immunity. Int. Immunol. 17, 1-14
13 Chang, C.P., Chang, J.Y., Wang, F.Y., and Chang, J.G. (1995). The effect of Chinese medicinal herb Zingiberis rhizoma extract on cytokine secretion by human peripheral blood mononuclear cells. J. Ethnopharmacol. 48, 13-19   DOI   ScienceOn
14 Saitoh, S., Akashi, S., Yamada, T., Tanimura, N., Kobayashi, M., Konno, K., Matsumoto, F., Fukase, K., Kusumoto, S., Nagai, Y., et al. (2004). Lipid A antagonist, lipid IVa, is distinct from lipid A in interaction with Toll-like receptor 4 (TLR4)-MD-2 and ligandinduced TLR4 oligomerization. Int. Immunol. 16, 961-969   DOI   ScienceOn
15 Youn, H.S., Lee, J.K., Choi, Y.J., Saitoh, S.I., Miyake, K., Hwang, D.H., and Lee, J.Y. (2008b). Cinnamaldehyde suppresses toll-like receptor 4 activation mediated through the inhibition of receptor oligomerization. Biochem. Pharmacol. 75, 494-502   DOI   ScienceOn
16 Rhode, J., Fogoros, S., Zick, S., Wahl, H., Griffith, K.A., Huang, J., and Liu, J.R. (2007). Ginger inhibits cell growth and modulates angiogenic factors in ovarian cancer cells. BMC Complement Altern Med. 7, 44   DOI   ScienceOn
17 Fitzgerald, K.A., McWhirter, S.M., Faia, K.L., Rowe, D.C., Latz, E., Golenbock, D.T., Coyle, A.J., Liao, S.M., and Maniatis, T. (2003). IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat. Immunol. 4, 491-496   DOI   ScienceOn
18 Surh, Y.J. (2002). Anti-tumor promoting potential of selected spice ingredients with antioxidative and anti-inflammatory activities: a short review. Food Chem. Toxicol. 40, 1091-1097   DOI   ScienceOn
19 Kim, J.J., Ahn, S.I., Lee, J.S., Yun, S.M., Lee, M., and Youn, H.S. (2008). Suppression of the expression of cyclooxygenase-2 induced by Toll-like receptor 2, 3, and 4 agonists by 6-shogaol. Korean J. Food SCI Technol. 40, 332-336
20 Youn, H.S., Lee, J.Y., Saitoh, S.I., Miyake, K., Kang, K.W., Choi, Y.J., and Hwang, D.H. (2006a). 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   DOI   ScienceOn
21 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., et al. (2002). TLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages. Nat. Immunol. 3, 392-398   DOI   ScienceOn
22 Takada, Y., Murakami, A., and Aggarwal, B.B. (2005). Zerumbone abolishes NF-kappaB and IkappaBalpha kinase activation leading to suppression of antiapoptotic and metastatic gene expression, upregulation of apoptosis, and downregulation of invasion. Oncogene 24, 6957-6969   DOI   ScienceOn
23 Ippoushi, K., Azuma, K., Ito, H., Horie, H., and Higashio, H. (2003). [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   DOI   ScienceOn
24 Youn, H.S., Lee, J.Y., Saitoh, S.I., Miyake, K., and Hwang, D.H. (2006c). Auranofin, as an anti-rheumatic gold compound, suppresses LPS-induced homodimerization of TLR4. Biochem. Biophys. Res. Commun. 350, 866-871   DOI   ScienceOn
25 Hajjar, A.M., O'Mahony, D.S., Ozinsky, A., Underhill, D.M., Aderem, A., Klebanoff, S.J., and Wilson, C.B. (2001). Cutting edge: functional interactions between toll-like receptor (TLR) 2 and TLR1 or TLR6 in response to phenol-soluble modulin. J. Immunol. 166, 15-19   DOI
26 Kim, S.O., Kundu, J.K., Shin, Y.K., Park, J.H., Cho, M.H., Kim, T.Y., and Surh, Y.J. (2005). [6]-Gingerol inhibits COX-2 expression by blocking the activation of p38 MAP kinase and NF-kappaB in phorbol ester-stimulated mouse skin. Oncogene 24, 2558-2567   DOI   ScienceOn
27 Thomson, M., Al-Qattan, K.K., Al-Sawan, S.M., Alnaqeeb, M.A., Khan, I., and Ali, M. (2002). The use of ginger (Zingiber officinale Rosc.) as a potential anti-inflammatory and antithrombotic agent. Prostaglandins Leukot Essent Fatty Acids 67, 475-478   DOI   ScienceOn