Anti-inflammatory Effects of Resveratrol, (-)-Epigallocatechin-3-gallate and Curcumin by the Modulation of Toll-like Receptor Signaling Pathways

Toll-like receptors 신호전달체계 조절을 통한 resveratrol, (-)-epigallocatechin-3-gallate, curcumin의 항염증 효과

  • Youn, Hyung-Sun (Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University)
  • 윤형선 (순천향대학교 의료과학대학 임상병리학과)
  • Published : 2007.10.31

Abstract

Toll-like receptors (TLRs) induce innate immune responses that are essential for host defenses against invading microbial pathogens, thus leading to the activation of adaptive immune responses. In general, TLRs have two major downstream signaling pathways: the MyD88- and TRIF-dependent pathways, which lead to the activation of $NF-{\kappa}B$ and IRF3. Numerous studies have demonstrated that certain phytochemicals possessing anti-inflammatory effects inhibit $NF-{\kappa}B$ activation induced by pro-inflammatory stimuli, including lipopolysaccharides and $TNF{\alpha}$. However, the direct molecular targets for such anti-inflammatory phytochemicals have not been fully identified. Identifying the direct targets of phytochemicals within the TLR pathways is important because the activation of TLRs by pro-inflammatory stimuli can induce inflammatory responses that are the key etiological conditions in the development of many chronic inflammatory diseases. In this paper we discuss the molecular targets of resveratrol, (-)-epigallocatechin-3-gallate (EGCG), and curcumin in the TLR signaling pathways. Resveratrol specifically inhibited the TRIF pathway in TLR3 and TLR4 signaling, by targetting TBK1 and RIP1 in the TRIF complex. Furthermore, EGCG suppressed the activation of IRF3 by targetting TBK1 in the TRIF-dependent signaling pathways. In contrast, the molecular target of curcumin within the TLR signaling pathways is the receptor itself, in addition to $IKK{\beta}$. Together, certain dietary phytochemicals can modulate TLR-derived signaling and inflammatory target gene expression, and in turn, alter susceptibility to microbial infection and chronic inflammatory diseases.

Keywords

References

  1. Ulevitch RJ. Molecular mechanisms of innate immunity. Immunol. Res. 21: 49-54 (2000) https://doi.org/10.1385/IR:21:2-3:49
  2. Ulevitch RJ. Therapeutics targeting the innate immune system. Nat. Rev. Immunol. 4: 512-520 (2004) https://doi.org/10.1038/nri1396
  3. Hoebe K, Janssen E, Beutler B. The interface between innate and adaptive immunity. Nat. Immunol. 5: 971-974 (2004) https://doi.org/10.1038/ni1004-971
  4. Akira S, Hemmi H. Recognition of pathogen-associated molecular patterns by TLR family. Immunol. Lett. 85: 85-95 (2003) https://doi.org/10.1016/S0165-2478(02)00228-6
  5. Liew FY, Xu D, Brint EK, O'Neill LA. Negative regulation of Toll-like receptor-mediated immune responses. Nat. Rev. Immunol. 5: 446-458 (2005) https://doi.org/10.1038/nri1630
  6. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi- Castagnoli P, Layton B, Beutler B. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: Mutations in Tlr4 gene. Science 282: 2085-2088 (1998) https://doi.org/10.1126/science.282.5396.2085
  7. Underhill DM, Ozinsky A, Hajjar AM, Stevens A, Wilson CB, Bassetti M, Aderem A. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 401: 811-815 (1999) https://doi.org/10.1038/44605
  8. Rezaei N. Therapeutic targeting of pattern-recognition receptors. Int. Immunopharmacol. 6: 863-869 (2006) https://doi.org/10.1016/j.intimp.2006.02.005
  9. Beutler B, Hoebe K, Du X, Ulevitch RJ. How we detect microbes and respond to them: The Toll-like receptors and their transducers. J. Leukocyte Biol. 74: 479-485 (2003) https://doi.org/10.1189/jlb.0203082
  10. Takeda K, Akira S. Toll-like receptors in innate immunity. Int. Immunol. 17: 1-14 (2005)
  11. Beutler B, Jiang Z, Georgel P, Crozat K, Croker B, Rutschmann S, Du X, Hoebe K. Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. Annu. Rev. Immunol. 24: 353-389 (2006) https://doi.org/10.1146/annurev.immunol.24.021605.090552
  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. 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
  16. Miyake K. Innate recognition of lipopolysaccharide by Toll-like receptor 4-MD-2. Trends Microbiol. 12: 186-92 (2004) https://doi.org/10.1016/j.tim.2004.02.009
  17. 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
  18. 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
  19. 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 factor- 3, in the Toll-like receptor signaling. J. Immunol. 171: 4304-4310 (2003) https://doi.org/10.4049/jimmunol.171.8.4304
  20. 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
  21. 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
  22. Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18: 6853-6866 (1999) https://doi.org/10.1038/sj.onc.1203239
  23. Ghosh S, Karin M. Missing pieces in the NF-kappaB puzzle. Cell 109: S81-S96 (2002) https://doi.org/10.1016/S0092-8674(02)00703-1
  24. 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
  25. 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
  26. 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
  27. Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nat. Rev. Cancer 3: 768-780 (2003) https://doi.org/10.1038/nrc1189
  28. Zingarelli B, Sheehan M, Wong HR. Nuclear factor-kappaB as a therapeutic target in critical care medicine. Crit. Care Med. 31: S105-S111 (2003) https://doi.org/10.1097/00003246-200301001-00015
  29. Hain R, Bieseler B, Kindl H, Schroder G, Stocker R. Expression of a stilbene synthase gene in Nicotiana tabacum results in synthesis of the phytoalexin resveratrol. Plant Mol. Biol. 15: 325-335 (1990) https://doi.org/10.1007/BF00036918
  30. Hain R, Reif HJ, Krause E, Langebartels R, Kindl H, Vornam B, Wiese W, Schmelzer E, Schreier PH, Stocker RH, Stenzel K. Disease resistance results from foreign phytoalexin expression in a novel plant. Nature 361: 153-156 (1993) https://doi.org/10.1038/361153a0
  31. Pervaiz S. Resveratrol: From grapevines to mammalian biology. FASEB J. 17: 1975-1985 (2003) https://doi.org/10.1096/fj.03-0168rev
  32. Kopp P. Resveratrol, a phytoestrogen found in red wine. A possible explanation for the conundrum of the 'French paradox'? Eur. J. Endocrinol. 138: 619-620 (1998) https://doi.org/10.1530/eje.0.1380619
  33. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425: 191-196 (2003) https://doi.org/10.1038/nature01960
  34. Bhat KP, Pezzuto JM. Cancer chemopreventive activity of resveratrol. Ann. NY Acad. Sci. 957: 210-229 (2002) https://doi.org/10.1111/j.1749-6632.2002.tb02918.x
  35. Martinez J, Moreno JJ. Effect of resveratrol, a natural polyphenolic compound, on reactive oxygen species and prostaglandin production. Biochem. Pharmacol. 59: 865-870 (2000) https://doi.org/10.1016/S0006-2952(99)00380-9
  36. Subbaramaiah K, Chung WJ, Michaluart P, Telang N, Tanabe T, Inoue H, Jang M, Pezzuto JM, Dannenberg AJ. Resveratrol inhibits cyclooxygenase-2 transcription and activity in phorbol ester-treated human mammary epithelial cells. J. Biol. Chem. 273: 21875-1882 (1998) https://doi.org/10.1074/jbc.273.34.21875
  37. Tsai SH, Lin-Shiau SY, Lin JK. Suppression of nitric oxide synthase and the down-regulation of the activation of NFkappaB in macrophages by resveratrol. Brit. J. Pharmacol. 126: 673-680 (1999) https://doi.org/10.1038/sj.bjp.0702357
  38. Wadsworth TL, Koop DR. Effects of the wine polyphenolics quercetin and resveratrol on pro-inflammatory cytokine expression in RAW 264.7 macrophages. Biochem. Pharmacol. 57: 941-949 (1999) https://doi.org/10.1016/S0006-2952(99)00002-7
  39. Chan MM, Mattiacci JA, Hwang HS, Shah A, Fong D. Synergy between ethanol and grape polyphenols, quercetin, and resveratrol, in the inhibition of the inducible nitric oxide synthase pathway. Biochem. Pharmacol. 60: 1539-1548 (2000) https://doi.org/10.1016/S0006-2952(00)00471-8
  40. Murakami A, Matsumoto K, Koshimizu K, Ohigashi H. Effects of selected food factors with chemopreventive properties on combined lipopolysaccharide- and interferon-gamma-induced IkappaB degradation in RAW264.7 macrophages. Cancer Lett. 195: 17-25 (2003) https://doi.org/10.1016/S0304-3835(03)00058-2
  41. Manna SK, Mukhopadhyay A, Aggarwal BB. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J. Immunol. 164: 6509-6519 (2000) https://doi.org/10.4049/jimmunol.164.12.6509
  42. Fujiki H. Green tea: Health benefits as cancer preventive for humans. Chem. Rec. 5: 119-132 (2005) https://doi.org/10.1002/tcr.20039
  43. Ikeda I, Tsuda K, Suzuki Y, Kobayashi M, Unno T, Tomoyori H, Goto H, Kawata Y, Imaizumi K, Nozawa A, Kakuda T. Tea catechins with a galloyl moiety suppress postprandial hypertriacylglycerolemia by delaying lymphatic transport of dietary fat in rats. J. Nutr. 135: 155-159 (2005)
  44. Wang X, Song KS, Guo QX, Tian WX. The galloyl moiety of green tea catechins is the critical structural feature to inhibit fatty-acid synthase. Biochem. Pharmacol. 66: 2039-2047 (2003) https://doi.org/10.1016/S0006-2952(03)00585-9
  45. Barthelman M, Bair WB 3rd, Stickland KK, Chen W, Timmermann BN, Valcic S, Dong Z, Bowden GT. (-)-Epigallocatechin-3- gallate inhibition of ultraviolet B-induced AP-1 activity. Carcinogenesis 19: 2201-2204 (1998) https://doi.org/10.1093/carcin/19.12.2201
  46. Yang F, de Villiers WJ, McClain CJ, Varilek GW. Green tea polyphenols block endotoxin-induced tumor necrosis factor-production and lethality in a murine model. J. Nutr. 128: 2334-2340 (1998)
  47. Wheeler DS, Catravas JD, Odoms K, Denenberg A, Malhotra V, Wong HR. Epigallocatechin-3-gallate, a green tea-derived polyphenol, inhibits IL-1 beta-dependent proinflammatory signal transduction in cultured respiratory epithelial cells. J. Nutr. 134: 1039- 1044 (2004)
  48. Yang TT, Koo MW. Inhibitory effect of Chinese green tea on endothelial cell-induced LDL oxidation. Atherosclerosis 148: 67- 73 (2000) https://doi.org/10.1016/S0021-9150(99)00239-7
  49. Metz N, Lobstein A, Schneider Y, Gosse F, Schleiffer R, Anton R, Raul F. Suppression of azoxymethane-induced preneoplastic lesions and inhibition of cyclooxygenase-2 activity in the colonic mucosa of rats drinking a crude green tea extract. Nutr. Cancer 38: 60-64 (2000) https://doi.org/10.1207/S15327914NC381_9
  50. Soriani M, Rice-Evans C, Tyrrell RM. Modulation of the UVA activation of haem oxygenase, collagenase and cyclooxygenase gene expression by epigallocatechin in human skin cells. FEBS Lett. 439: 253-257 (1998) https://doi.org/10.1016/S0014-5793(98)01387-8
  51. Chan MM, Fong D, Ho CT, Huang HI. Inhibition of inducible nitric oxide synthase gene expression and enzyme activity by epigallocatechin gallate, a natural product from green tea. Biochem. Pharmacol. 54: 1281-1286 (1997) https://doi.org/10.1016/S0006-2952(97)00504-2
  52. Lin YL, Lin JK. (-)-Epigallocatechin-3-gallate blocks the induction of nitric oxide synthase by down-regulating lipopolysaccharide- induced activity of transcription factor nuclear factor-kappaB. Mol. Pharmacol. 52: 465-472 (1997) https://doi.org/10.1124/mol.52.3.465
  53. Pan MH, Lin-Shiau SY, Ho CT, Lin JH, Lin JK. Suppression of lipopolysaccharide-induced nuclear factor-kappaB activity by theaflavin-3,3'-digallate from black tea and other polyphenols through down-regulation of IkappaB kinase activity in macrophages. Biochem. Pharmacol. 59: 357-367 (2000) https://doi.org/10.1016/S0006-2952(99)00335-4
  54. Yang F, Oz HS, Barve S, de Villiers WJ, McClain CJ, Varilek GW. The green tea polyphenol (-)-epigallocatechin-3-gallate blocks nuclear factor-kappa B activation by inhibiting I kappa B kinase activity in the intestinal epithelial cell line IEC-6. Mol. Pharmacol. 60: 528-533 (2001)
  55. Payton F, Sandusky P, Alworth WL. NMR study of the solution structure of curcumin. J. Nat. Prod. 70: 143-146 (2007) https://doi.org/10.1021/np060263s
  56. Sharma RA, Gescher AJ, Steward WP. Curcumin: The story so far. Eur. J. Cancer 41: 1955-1968 (2005) https://doi.org/10.1016/j.ejca.2005.05.009
  57. 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
  58. 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 I-kappa B kinase activity. J. Immunol. 163: 3474-3483 (1999)
  59. 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
  60. Kang G, Kong PJ, Yuh YJ, Lim SY, Yim SV, Chun W, Kim SS. Curcumin suppresses lipopolysaccharide-induced cyclooxygenase- 2 expression by inhibiting activator protein 1 and nuclear factor $\kappa$B bindings in BV2 microglial cells. J. Pharmacol. Sci. 94: 325- 328 (2004) https://doi.org/10.1254/jphs.94.325
  61. Zhang H, Tay PN, Cao W, Li W, Lu J. Integrin-nucleated Tolllike 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
  62. Jeong WS, Kim IW, Hu R, Kong AN. Modulatory properties of various natural chemopreventive agents on the activation of NFkappaB signaling pathway. Pharm. Res. 21: 661-670 (2004) https://doi.org/10.1023/B:PHAM.0000022413.43212.cf
  63. 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
  64. 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
  65. 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
  66. 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
  67. Singh S, Aggarwal BB. Activation of transcription factor NFkappa B is suppressed by curcumin (diferuloylmethane). J. Biol. Chem. 270: 24995-25000 (1995) https://doi.org/10.1074/jbc.270.42.24995
  68. 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