Korean Journal of Food Science and Technology (한국식품과학회지)

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

Anti-cancer and Anti-inflammatory Effects of Curcumin by the Modulation of Toll-like Receptor 2, 3 and 4

Toll-like receptor 2, 3, 4의 신호전달체계 조절을 통한 curcumin의 항암${\cdot}$항염증 효과

  • Kang, Soon-Ah (Department of Fermented Food Science, Seoul University of Venture and Information) ;
  • Hwang, Daniel (USDA, ARS, Western Human Nutrition Research Center and Department of Nutrition, University of California) ;
  • Youn, Hyung-Sun (Department of Biomedical Laboratory Science, College of Medical Sciences, SoonChunHyang University)
  • 강순아 (서울벤처정보대학원대학교 발효식품과학과) ;
  • ;
  • 윤형선 (순천향대학교 의료과학대학 임상병리학과)
  • Published : 2007.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

Toll-like receptors induce innate immune responses recognizing conserved microbial structural molecules that are known as pathogen-associated molecular patterns (PAMPs). Ligand-induced homotypic oligomerization was found to proceed in LPS-induced activation of TLR4 signaling pathways. TLR2 is known to heterodimerize with TLR1 or TLR6 and recognize diacyl- or triacyl-lipopeptide, respectively. These results suggest that ligand-induced receptor dimerization of TLR4 and TLR2 is required for the activation of downstream signaling pathways. Therefore, receptor dimerization may be one of the first lines of regulation in the activation of TLR-mediated signaling pathways and induction of subsequent innate and adaptive immune responses. Here, we report biochemical evidence that curcumin from the plant Curcuma longa inhibits activation of $NF-{\kappa}B$, expression of COX-2, and dimerization of TLRs induced by TLR2, TLR3 and TLR4 agonists. These results imply that curcumin can modulate the activation of TLRs and subsequent immune/inflammatory responses induced by microbial pathogens.

TLRs는 병원균이 숙주의 몸 속에 들어 왔을 때, 병원균들이 가지고 있는 독특한 구조를 인식하여 선천성 면역반응과 뒤이어 후천성 면역반응을 유도하는 중요한 역할을 한다. 우리는 이번 실험을 통하여 curcumin이 선행연구에서 밝혀낸 TLR4 뿐만 아니라 TLR2와 TLR6 그리고 TLR3를 또한 분자학적인 타깃으로 할 수 있다는 것을 알아내었다. Curcumin이 MALP-2(TLR2,6 agonist)에 의해서 유도된 IRAK-1 degradation을 억제시켰다. 이러한 결과는 curcumin의 분자학적인 타깃이 IRAK-1위에 놓여 있으며, TLR2와 TLR6가 될 것이라는 가능성을 제시해 준다고 할 수 있다. 또한 curcumin은 viral 자극제인 poly[I:C](TLR3 agonist)에 의해서 유도된 IRF3나 $NF-{\kappa}B$ 활성화를 억제하였지만, TRIF에 의해서 유도된 IRF3 활성화는 억제시키지를 못하였다. 이러한 결과 또한 TLR3 자체가 curcumin의 분자학적인 타깃이라는 가능성을 제시해 준다고 할 수 있겠다. 이러한 결과를 종합해 볼때, curcumin의 분자학적인 타깃이 $IKK{\beta}$ 이외에 모든 TLRs가 될 수 있다는 가능성을 제시해 준다고 할 수 있겠다. 이러한 결과는 curcumin이 그람음성균 뿐만이 아니라 바이러스나 박테리아 등 여러 병원균들로부터 유도되는 염증반응이나 만성적인 질병들을 조절할 수 있다는 것을 보여주는 결과라 할 수 있겠다.

Keywords

References

  1. Takeda K, Akira S. Toll-like receptors in innate immunity. Int. Immunol. 17: 1-14 (2005)
  2. Medzhitov R. Toll-like receptors and innate immunity. Nat. Rev. Immunol. 1: 135-145 (2001) https://doi.org/10.1038/35100529
  3. 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
  4. 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
  5. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388: 394-397 (1997) https://doi.org/10.1038/41131
  6. Hajjar AM, O'Mahony DS, Ozinsky A, Underhill DM, Aderem A, Klebanoff SJ, Wilson CB. 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 (2001) https://doi.org/10.4049/jimmunol.166.1.15
  7. 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 factor3, in the Toll-like receptor signaling. J. Immunol. 171: 4304-4310 (2003) https://doi.org/10.4049/jimmunol.171.8.4304
  8. 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
  9. 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
  10. 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
  11. Youn HS, Saitoh SI, Miyake K, Hwang DH. Inhibition of homodimerization of Toll-like receptor 4 by curcumin. Biochem. Phannacol. 72: 62-69 (2006) https://doi.org/10.1016/j.bcp.2006.03.022
  12. Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nat. Rev. Cancer. 3: 768-780 (2003) https://doi.org/10.1038/nrc1189
  13. Zingarelli B, Sheehan M, Wong HR. Nuclear factor-kappa B as a therapeutic target in critical care medicine. Crit. Care Med. 31: S105-S111 (2003) https://doi.org/10.1097/00003246-200301001-00015
  14. 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
  15. Pan MH, Lin-Shiau SY, Lin JK. Comparative studies on the suppression of nitric oxide synthase by curcumin and its hydrogenated metabolites through down-regulation of IkappaB kinase and NFkappaB activation in macrophages. Biochem. Pharmacol. 60: 1665-1676 (2000) https://doi.org/10.1016/S0006-2952(00)00489-5
  16. Jobin C, Bradham CA, Russo MP, Juma B, Narula AS, Brenner DA, Sartor RB. Curcumin blocks cytokine-mediated NF-kappa B activation and proinflammatory gene expression by inhibiting inhibitory factor l-kappa B kinase activity. J. Immunol. 163: 3474-3483 (1999)
  17. Singh S, Aggarwal BB. Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) [corrected]. J. Biol. Chem. 270: 24995-25000 (1995) https://doi.org/10.1074/jbc.270.42.24995
  18. Brouet I, Ohshima H. Curcumin, an anti-tumour promoter and anti-inflammatory agent, inhibits induction of nitric oxide synthase in activated macrophages. Biochem. Bioph. Res. Co. 206: 533-540 (1995) https://doi.org/10.1006/bbrc.1995.1076
  19. Saitoh S, Akashi S, Yamada T, Tanimura N, Kobayashi M, Konno K, Matsumoto F, Fukase K, Kusumoto S, Nagai Y, Kusumoto Y, Kosugi A, Miyake K. Lipid A antagonist, lipid IVa, is distinct from lipid A in interaction with Toll-like receptor 4 (TLR4)-MD-2 and ligand-induced TLR4 oligomerization. Int. Immunol. 16: 961-969 (2004) https://doi.org/10.1093/intimm/dxh097
  20. Miyake K. Innate recognition of lipopolysaccharide by Toll-like receptor 4-MD-2. Trends Microbiol. 12: 186-192 (2004) https://doi.org/10.1016/j.tim.2004.02.009
  21. Takeuchi O, Kawai T, Muhlradt PF, Morr M, Radolf JD, Zychlinsky A, Takeda K, Akira S. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int. Immunol. 13: 933-940 (2001) https://doi.org/10.1093/intimm/13.7.933
  22. Takeuchi O, Sato S, Horiuchi T, Hoshino K, Takeda K, Dong Z, Modlin RL, Akira S. Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J. Immunol. 169: 10-14 (2002) https://doi.org/10.4049/jimmunol.169.1.10
  23. Lee JY, Zhao L, Youn HS, Weatherill AR, Tapping R, Feng L, Lee WH, Fitzgerald KA, Hwang DH. Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1. J. BioI. Chem. 279: 16971-16979 (2004) https://doi.org/10.1074/jbc.M312990200
  24. Lee JY, Ye J, Gao Z, Youn HS, Lee WH, Zhao L, Sizemore N, Hwang DH. Reciprocal modulation of Toll-like receptor-s signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/ AKT by saturated and polyunsaturated fatty acids. J. Biol. Chem. 278: 37041-37051 (2003) https://doi.org/10.1074/jbc.M305213200
  25. Rhee SH, Hwang D. Murine Toll-like receptor 4 confers lipopolysaccharide responsiveness as determined by activation of NF kappa B and expression of the inducible cyclooxygenase. J. Biol. Chem. 275: 34035-34040 (2000) https://doi.org/10.1074/jbc.M007386200
  26. Zhang H, Tay PN, Cao W, Li W, Lu J. Integrin-nucleated Toll-like receptor (TLR) dimerization reveals subcellular targeting of TLRs and distinct mechanisms of TLR4 activation and signaling. FEBS Lett. 532: 171-176 (2002) https://doi.org/10.1016/S0014-5793(02)03669-4
  27. Tao X, Xu Y, Zheng Y, Beg AA, Tong L. An extensively associated dimer in the structure of the C713S mutant of the TIR domain of human TLR2. Biochem. Bioph. Res. Co. 299: 216-221 (2002) https://doi.org/10.1016/S0006-291X(02)02581-0