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Inflammation Research

, Volume 67, Issue 7, pp 597–608 | Cite as

Genistein modulates the expression of Toll-like receptors in experimental autoimmune encephalomyelitis

  • Alyria Teixeira Dias
  • Sandra Bertelli Ribeiro de Castro
  • Caio César de Souza Alves
  • Marcilene Gomes Evangelista
  • Luan Cristian da Silva
  • Daniele Ribeiro de Lima Reis
  • Marco Antonio Machado
  • Maria Aparecida Juliano
  • Ana Paula Ferreira
Original Research Paper
  • 111 Downloads

Abstract

Objective and design

The present work investigates the modulation of experimental autoimmune encephalomyelitis (EAE) using genistein before the EAE induction.

Material

Female C57BL/6 mice (n = 96 mice/experiment), 4–6 weeks old, were used to induce the EAE. The mice were divided into three experimental groups: non-immunized group, immunized group (EAE), and immunized and treated with genistein group (Genistein).

Treatment

Genistein was used at a dose of 200 mg/kg s.c. and were initiated 2 days before the immunization and continued daily until day 6 postimmunization.

Methods

Animals were monitored daily for clinical signs of EAE up to day 21. Inflammatory infiltration, demyelination, Toll-like receptor (TLR) expression, cytokines and transcription factors were analyzed in spinal cords.

Results

The present study demonstrates, for the first time, the genistein ability to modulate the factors involved in the innate immune response in the early stages of EAE. The genistein therapy delayed the onset of the disease, with reduced inflammatory infiltration and demyelination. In addition, the expression of TLR3, TLR9 and IFN-β were increased in genistein group, with reduction in the factors of TH1 and Th17 cells.

Conclusion

These findings shed light on the potential of genistein as a prophylactic strategy for multiple sclerosis (MS) prevention.

Keywords

Multiple sclerosis Experimental autoimmune encephalomyelitis IFN-β Toll-like Immune response 

Notes

Acknowledgements

This work was supported in part by Grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico [Grant Numbers 481459/2009-0, 303369/2009-4, 306575/2012-4, 470768/2013-4, and 306768/2015-1]; Fundação de Amparo à Pesquisa do Estado de Minas Gerais [grant numbers 02236/10, PPM 0216/10 and PPM 00269-14]; and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior [Grant Number PNPD-2882/2011].

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

References

  1. 1.
    Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol. 2007;61:288–99.CrossRefPubMedGoogle Scholar
  2. 2.
    O’Gorman C, Lin R, Stankovich J, Broadley SA. Modelling genetic susceptibility to multiple sclerosis with family data. Neuroepidemiology. 2013;40:1–12.CrossRefPubMedGoogle Scholar
  3. 3.
    Rao P, Segal BM. Experimental autoimmune encephalomyelitis. Methods Mol Biol. 2012;900:363–80.CrossRefPubMedGoogle Scholar
  4. 4.
    Touil T, Fitzgerald D, Zhang GX, Rostami A, Gran B. Cutting Edge: TLR3 stimulation suppresses experimental autoimmune encephalomyelitis by inducing endogenous IFN-beta. J Immunol. 2006;11:7505–9.CrossRefGoogle Scholar
  5. 5.
    Gooshe M, Abdolghaffari AH, Gambuzza ME, Rezaei N. The role of Toll-like receptors in multiple sclerosis and possible targeting for therapeutic purposes. Rev Neurosci. 2014;25:713–39.PubMedGoogle Scholar
  6. 6.
    Evangelista MG, Castro SBR, Alves CC, Dias AT, Souza VW, Reis LB, Silva LC, Castañon MC, Farias RE, Juliano MA, Ferreira AP. Early IFN-γ production together with decreased expression of TLR3 and TLR9 characterizes EAE development conditional on the presence of myelin. Autoimmunity. 2016;49:258–67.CrossRefPubMedGoogle Scholar
  7. 7.
    Fox EJ. Mechanism of action of mitoxantrone. Neurology. 2004;63:15–8.CrossRefGoogle Scholar
  8. 8.
    Burks J. Interferon-beta1β for multiple sclerosis. Expert Ver Neurother. 2005;5:153–64.CrossRefGoogle Scholar
  9. 9.
    Goverman J. Autoimmune T cell response in the central nervous system. Nat Rev Immunol. 2009;9:393–407.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Garay L, Gonzalez Deniselle MC, Gierman L, Meyer M, Lima A, Roig P, de Nicola AF. Steroid protection in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Neuroimmunomodulation. 2008;15:76–83.CrossRefPubMedGoogle Scholar
  11. 11.
    Lélu K, Laffont S, Delpy L, Paulet PE, Périnat T, Tschanz SA, Pelletier L, Engelhardt B, Guéry JC. Estrogen receptor α signaling in T lymphocytes is required for estradiol-mediated inhibition of Th1 and Th17 cell differentiation and protection against experimental autoimmune encephalomyelitis. J Immunol. 2011;187:2386–93.CrossRefPubMedGoogle Scholar
  12. 12.
    Spanier JA, Nashold FE, Mayne CG, Nelson CD, Hayes CE. Vitamin D and estrogen synergy in Vdr-expressing CD4(+) T cells is essential to induce Helios(+)FoxP3(+) T cells and prevent autoimmune demyelinating disease. J Neuroimmunol. 2015;286:48–58.CrossRefPubMedGoogle Scholar
  13. 13.
    De Paula ML, Rodrigues DH, Teixeira HC, Barsante MM, Souza MA, Ferreira AP. Genistein down-modulates pro-inflammatory cytokines and reverses clinical signs of experimental autoimmune encephalomyelitis. Int Immunopharmacol. 2008;8:1291–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Castro SBR, Junior COR, Alves CCS, Dias AT, Alves LL, Mazzoccoli L, Mesquita FP, Figueiredo NS, Juliano MA, Castañon MC, Gameiro J, Almeida MV, Teixeira HC, Ferreira AP. Immunomodulatory effects and improved prognosis of experimental autoimmune encephalomyelitis after O-tetradecanoyl-genistein treatment. Int Immunopharmacol. 2012;12:465–70.CrossRefPubMedGoogle Scholar
  15. 15.
    Jahromi SR, Arrefhosseini SR, Ghaemi A, Alizadeh A, Sabetghadam F, Togha M. Effect of oral genistein administration in early and late phases of allergic encephalomyelitis. Iran J Basic Med Sci. 2014;17:509–15.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Dijsselbloem N, Goriely S, Albarani V, Gerlo S, Francoz S, Marine JC, Goldman M, Haegeman G, Vanden Berghe W. A critical role for p53 in the control of NF-kappa B-dependent gene expression in TLR-4-stimulated dendritic cells exposed to genistein. J Immunol. 2007;178:5048–57.CrossRefPubMedGoogle Scholar
  17. 17.
    Byun EB, Sung NY, Yang MS, Lee BS, Song DS, Park JN, Kim JH, Jang BS, Choi DS, Park SH, Yu YB, Byun EH. Anti-inflammatory effect of gamma-irradiated genistein through inhibition of NF-κB and MAPK signaling pathway in lipopolysaccharide-induced macrophages. Food Chem Toxicol. 2014;74:255–64.CrossRefPubMedGoogle Scholar
  18. 18.
    Kim DH, Jung WS, Kim ME, Lee HW, Youn HY, Seon JK, Lee HN, Lee JS. Genistein inhibits pro-inflammatory cytokines in human mast cell activation through the inhibition of the ERK pathway. Int J Mol Med. 2014;34:1669–74.CrossRefPubMedGoogle Scholar
  19. 19.
    Buathong N, Poonyachoti S, Deachapunya C. Isoflavone genistein modulates the protein expression of toll-like receptors in cancerous human endometrial cells. J Med Assoc Thai. 2015;98:S31–8.Google Scholar
  20. 20.
    Jeong JW, Lee HH, Han MH, Kim GY, Kim WJ, Choi YH. Anti-inflammatory effects of genistein via suppression of the toll-like receptor 4-mediated signaling pathway in lipopolysaccharide-stimulated BV2 microglia. Chem Biol Interact. 2014;212:30–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Zhou X, Yuan L, Zhao X, Hou C, Ma W, Yu H, Xiao R. Genistein antagonizes inflammatory damage induced by β-amyloid peptide in microglia through TLR4 and NF-Κb. Nutrition. 2014;30:90–5.CrossRefPubMedGoogle Scholar
  22. 22.
    Xiao J, Liu W, Chen Y, Deng W. Recombinant human PDCD5 (rhPDCD5) protein is protective in a mouse model of multiple sclerosis. J Neuroinflammation. 2015;12:117.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Abdul-Majid KB, Wefer J, Stadelmann C, Stefferl A, Lassmann H, Olsson T, Harris RA. Comparing the pathogenesis of experimental autoimmune encephalomyelitis in CD4-/- and CD8-/- DBA/1 mice defines qualitative roles of different T cell subsets. J Neuroimmunol. 2003;141:10–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Blanco YC, Farias AS, Goelnitz U, Lopes SC, Arrais-silva WW, Carvalho BO, Amino R, Wunderlich G, Santos LM, Giorgio S, Costa FT. Hyperbaric oxygen prevents early death caused by experimental cerebral malaria. Plos One. 2008;3:e3126.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Chrzan BG, Bradford PG. Phytoestrogens activate estrogen receptor beta1 and estrogenic responses in human breast and bone cancer cell lines. Mol Nutr Food Res. 2007;51:171–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Moran J, Garrido P, Alonso A, Cabello E, Gonzalez C. 17beta- Estradiol and genistein acute treatments improve some cerebral cortex homeostasis aspects deteriorated by aging in female rats. Exp Gerontol. 2013;48:414–21.CrossRefPubMedGoogle Scholar
  27. 27.
    Rietjens IMCM., Louisse J, Beekmann K. The potential health effects of dietary Phytoestrogens. Br J Pharmacol. 2016;174:1263–80.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    de la Parra C, Castillo-Pichardo L, Cruz-Collazo A, Cubano L, Redis R, Calin GA, Dharmawardhane S. Soy isoflavone genistein-mediated downregulation of miR-155 contributes to the anticancer effects of genistein. Nutr Cancer. 2016;68:154–64.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Dias AT, Castro SBR, Alves CS, Mesquita FP, Figueiredo NS, Evangelista MG, Castanon MCMN., Juliano MA, Ferreira AP. Different MOG35-55 concentrations induce distinguishable inflammation through early regulatory response by IL-10 and TGF-β in mice CNS despite unchanged clinical course. Cell Immunol. 2015;293:87–94.CrossRefPubMedGoogle Scholar
  30. 30.
    Marta M, Andersson A, Isaksson M, Kämpe O, Lobell A. Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis. Eur J Immunol. 2008;38:565–75.CrossRefPubMedGoogle Scholar
  31. 31.
    Zhang ZY, Zhang Z, Schluesener HJ. Toll-like receptor-2, CD14 and heat-shock protein 70 in inflammatory lesions of rat experimental autoimmune neuritis. Neuroscience. 2009;159:136–42.CrossRefPubMedGoogle Scholar
  32. 32.
    Reynolds JM, Martinez GJ, Chung Y, Dong C. Toll-like receptor 4 signaling in T cells promotes autoimmune inflammation. Proc Natl Acad Sci USA. 2012;109:13064–9.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Miranda-Hernandez S, Baxter AG. Role of toll-like receptors in multiple sclerosis. Am J Clin Exp Immunol. 2013;2:75–93.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Jack CS, Arbour N, Manusow J, Montgrain V, Blain M, McCrea E, Shapiro A, Antel JP. TLR signaling tailors innate immune responses in human microglia and astrocytes. J Immunol. 2005;175:4320–30.CrossRefPubMedGoogle Scholar
  35. 35.
    Hegen H, Auer M, Deisenhammer F. Pharmacokinetic consideration in the treatment of multiple sclerosis with interferon-β. Expert Opin Drug Metab Toxicol. 2015;11:1803–19.CrossRefPubMedGoogle Scholar
  36. 36.
    Guo B, Chang EY, Cheng G. The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice. J Clin Invest. 2008;118:1680–90.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Khorooshi R, Mørch MT, Holm TH, Berg CT, Dieu RT, Dræby D, Issazadeh-Navikas S, Weiss S, Lienenklaus Owens T. Induction of endogenous Type I interferon within the central nervous system plays a protective role in experimental autoimmune encephalomyelitis. Acta Neuropathol. 2015;130:107–18.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Rossi B, Angiari S, Zenaro E, Budui SL, Constantin G. Vascular inflammation in central nervous system diseases: adhesion receptors controlling leukocyte-endothelial interactions. J Leukoc Biol. 2011;89:539–56.CrossRefPubMedGoogle Scholar
  39. 39.
    Kanhere A, Hertweck A, Bhatia U, Gökmen MR, Perucha E, Jackson I, Lord GM, Jenner RG. T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements. Nat Commun. 2012;3:1268.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Schulz EG, Mariani L, Radbruch A, Höfer A. Sequential polarization and imprinting of type 1 T helper lymphocytes by interferon-gamma and interleukin-12. Immunity. 2009;30:673–83.CrossRefPubMedGoogle Scholar
  41. 41.
    Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell. 2000;100:655–69.CrossRefPubMedGoogle Scholar
  42. 42.
    Bettelli B, Sullivan B, Szabo SJ, Sobel RA, Glimcher LH, Kuchroo VK. Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J Exp Med. 2004;200:79–87.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Lovett-Racke AE, Rocchini AE, Choy J, Northrop SC, Hussain RZ, Ratts RB, Sikder D, Racke MK. Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes. Immun. 2004;21:719–31.CrossRefGoogle Scholar
  44. 44.
    Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol. 2006;177:566–73.CrossRefPubMedGoogle Scholar
  45. 45.
    Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, Giuliani F, Arbour N, Becher B, Prat A. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med. 2007;13:1173–5.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Yang C, He D, Yin C, Tan J. Inhibition of interferon regulatory factor 4 suppresses Th1 and Th17 cell differentiation and ameliorates experimental autoimmune encephalomyelitis. Scand J Immunol. 2015;82:345–51.CrossRefPubMedGoogle Scholar
  47. 47.
    Martinez NE, Sato F, Omura S, Kawai E, Takahashi S, Yoh K, Tsunoda I. RORγt, but not T-bet, overexpression exacerbates an autoimmune model for multiple sclerosis. J Neuroimmunol. 2014;276:142–9.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Ichiyama K, Yoshida H, Wakabayashi Y, Chinen T, Saeki K, Nakaya M, Takaesu G, Hori S, Yoshimura A, Kobayashi T. Foxp3 inhibits RORgammat-mediated IL-17A mRNA transcription through direct interaction with RORgammat. J Biol Chem. 2008;283:17003–8.CrossRefPubMedGoogle Scholar
  49. 49.
    Wraith DC, Nicolson KS, Whitley NT. Regulatory CD4 + T cells and the control of autoimmune disease. Curr Opin Immunol. 2004;16:695–701.CrossRefPubMedGoogle Scholar
  50. 50.
    Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133:775–87.CrossRefPubMedGoogle Scholar
  51. 51.
    Andres S, Abraham K, Appel KE, Lampen A. Risks and benefits of dietary isoflavones for cancer. Crit Rev Toxicol. 2011;41:463–506.CrossRefPubMedGoogle Scholar
  52. 52.
    Chatterjee G, Roy D, Khemka VK, Chattopadhyay M, Chakrabarti S. Genistein, the isoflavone in soybean, causes amyloid beta peptide accumulation in human neuroblastoma cell line: implications in Alzheimer’s disease. Aging Dis. 2015;6:456–65.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Singh P, Sharma S, Rath SK. Genistein induces deleterious effects during its acute exposure in Swiss mice. Biomed Res Int. 2014;2014:619617.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Alyria Teixeira Dias
    • 1
  • Sandra Bertelli Ribeiro de Castro
    • 2
  • Caio César de Souza Alves
    • 3
  • Marcilene Gomes Evangelista
    • 1
  • Luan Cristian da Silva
    • 1
  • Daniele Ribeiro de Lima Reis
    • 4
  • Marco Antonio Machado
    • 4
  • Maria Aparecida Juliano
    • 5
  • Ana Paula Ferreira
    • 1
  1. 1.IMUNOCET, Department of Parasitology, Microbiology and Immunology, Institute of Biological SciencesFederal University of Juiz de ForaJuiz de ForaBrazil
  2. 2.Department of PharmacyFederal University of Juiz de ForaGovernador ValadaresBrazil
  3. 3.Faculty of MedicineFederal University of the Valleys of Jequitinhonha and MucuriTeófilo OtoniBrazil
  4. 4.Empresa Brasileira de Pesquisa AgropecuáriaJuiz de ForaBrazil
  5. 5.Department of BiophysicsFederal University of São PauloSão PauloBrazil

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