Skip to main content
SpringerLink
Log in

Quercetin, a Flavonoid Phytoestrogen, Ameliorates Experimental Allergic Encephalomyelitis by Blocking IL-12 Signaling Through JAK-STAT Pathway in T Lymphocyte

Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated inflammatory demyelinating autoimmune disease model of multiple sclerosis (MS). Quercetin (3,3'4',5,7-pentahydroxy flavone) is a flavonoid phytoestrogen that has profound anticancer and anti-inflammatory activities. In this study, we show that in vivo treatment of SJL/J mice with quercetin (i.p. 50 or 100 μg every other day) ameliorates EAE in association with the inhibition of IL-12 production and neural antigen-specific Th1 differentiation. In vitro treatment of activated T cells with quercetin blocks IL-12-induced tyrosine phosphorylation of JAK2, TYK2, STAT3, and STAT4, resulting in a decrease in IL-12-induced T cell proliferation and Th1 differentiation. These findings highlight the fact that quercetin ameliorates EAE by blocking IL-12 signaling and Th1 differentiation and suggest its use in the treatment of MS and other Th1 cell-mediated autoimmune diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

REFERENCES

  1. Dean G: How many people in the world have MS? Neuroepidemiology 13: 1–7, 1994

    PubMed  Google Scholar 

  2. Steinman L, Martin M, Bernard C, Conlon P, Oksenberg JR: Multiple sclerosis: Deeper understanding of its pathogenesis reveals new targets for therapy. Annu Rev Neurosci 25: 491–505, 2002

    PubMed  Google Scholar 

  3. Clegg A, Bryant J: Immunomodulatory drugs for multiple sclerosis: A systematic review of clinical and cost effectiveness. Expert Opin Pharmacother 2: 623–639, 2001

    PubMed  Google Scholar 

  4. Donoghue S, Greenlees C: Drugs in development for the treatment of multiple sclerosis: Antigen non-specific specific therapies, an update. Expert Opin Invest Drugs 9: 167–171, 2000

    Google Scholar 

  5. Owens T, Sriram S: The immunology of MSand of its animal model, EAE. Neurol Clin 13: 51–73, 1995

    PubMed  Google Scholar 

  6. Gold R, Hartung HP, Toyka KV: Animal models for autoimmune demyelinating disorders of the nervous system. Mol Med Today 6: 88–91, 2000

    PubMed  Google Scholar 

  7. Natarajan C, Bright JJ: Peroxisome proliferator-activated receptor-gamma agonists inhibit experimental allergic encephalomyelitis by blocking IL-12 production, IL-12 signaling and Th1 differentiation. Genes Immun 3: 59–70, 2002

    PubMed  Google Scholar 

  8. Natarajan C, Bright JJ: Curcumin inhibits experimental allergic en-cephalomyelitis by blocking IL-12 signaling through JAK-STAT pathway in T cells and differentiation of neural antigen specific Th1 cells. J Immunol 169: 6506–6513, 2002

    Google Scholar 

  9. Whitacre CC, Reingold SC, O'Looney PA: A gender gap in autoimmunity. Science 283: 1277–1278, 1999

    PubMed  Google Scholar 

  10. Darlington C: Multiple sclerosis and gender. Curr Opin Invest Drugs 3: 911–914, 2002

    Google Scholar 

  11. Schuna AA: Autoimmune rheumatic diseases in women. J Am Pharm Assoc 42: 612–23, 2002

    Google Scholar 

  12. Bansil S, Lee HJ, Jindal S, Holtz CR, Cook SD: Correlation between sex hormones and magnetic resonance imaging lesions in multiple sclerosis. Acta Neurol Scand 99: 91–94, 1999

    PubMed  Google Scholar 

  13. Castagnetta L, Granata OM, Traina A, Cocciadiferro L, Saetta A, Stefano R, Cutolo M, Carruba G: A role for sex steroids in autoimmune diseases: A working hypothesis and supporting data. Ann NY Acad Sci 966: 193–203, 2002

    PubMed  Google Scholar 

  14. Hernan MA, Hohol MJ, Olek MJ, Spiegelman D, Ascherio A: Oral contraceptives and the incidence of multiple sclerosis. Neurology 55: 848–854, 2000

    PubMed  Google Scholar 

  15. James WH: Oral contraceptives, rheumatoid arthritis, and androgens. Ann Rheum Dis 62: 279, 2003

    PubMed  Google Scholar 

  16. Keith AB: Sex difference in Lewis rats in the incidence of recurrent experimental allergic encephalomyelitis. Nature 272: 824–825, 1978

    PubMed  Google Scholar 

  17. Jansson L, Olsson T, Holmdahl R: Estrogen induces a potent suppression of experimental autoimmune encephalomyelitis and collagen-induced arthritis in mice. J Neuroimmunol 53: 203–207, 1994

    PubMed  Google Scholar 

  18. Matejuk A, Adlard K, Zamora A, Silverman M, Vandenbark AA, Offner H: 17 Beta-estradiol inhibits cytokine, chemokine, and chemokine receptor mRNAexpression in the central nervous system of female mice with experimental autoimmune encephalomyelitis. J Neurosci Res 65: 529–542, 2001

    PubMed  Google Scholar 

  19. Katzenellenbogen BS, Choi I, Delage-Mourroux R, Ediger TR, Martini PG, Montano M, Sun J, Weis K, Katzenellenbogen JA: Molecular mechanisms of estrogen action: Selective ligands and receptor pharmacology. J Steroid Biochem Mol Biol 74: 279–285, 2000

    PubMed  Google Scholar 

  20. Paech K, Webb P, Kuiper GG, Nilsson S, Gustafsson J, Kushner PJ, Scanlan TS: Differential ligand activation of estrogen receptors ER-alpha and ERbeta at AP1 sites. Science 277: 1508–1510, 1997

    Google Scholar 

  21. Elliston JF, Fawell SE, Klein-Hitpass L, Tsai SY, Tsai MJ, Parker MG, O'Malley BW: Mechanism of estrogen receptor-dependent transcription in a cell-free system. Mol Cell Biol 10: 6607–6612, 1990

    PubMed  Google Scholar 

  22. Davis SR, Dalais FS, Simpson ER, Murkies AL: Phytoestrogens in health and disease. Recent Prog Horm Res 54: 185–211, 1999

    PubMed  Google Scholar 

  23. Breinholt V, Hossaini A, Svendsen GW, Brouwer C, Nielsen E: Estrogenic activity of flavonoids in mice, the importance of estrogen receptor distribution, metabolism and bioavailability. Food Chem Toxicol 38: 555–564, 2000

    PubMed  Google Scholar 

  24. Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, van der Burg V, Gustafsson JA: Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinol 139: 4252–4263, 1998

    Google Scholar 

  25. Belcher SM, Zsarnovszky A: Estrogenic actions in the brain: Estrogen, phytoestrogens and rapid intracellular signaling mechanisms. J Pharmacol Exp Ther 299: 408–414, 2001

    PubMed  Google Scholar 

  26. Collins-Burow BM, Burow ME, Duong N, McLachla JA: Estrogenic and antiestrogenic activities of flavonoid phytochemicals through estrogen receptor binding-dependent and-independent mechanisms. Nutr Cancer 38: 229–244, 2000

    PubMed  Google Scholar 

  27. Hollman PC, Hertog MG, Katan MB: Role of dietary flavonoids in protection against cancer and coronary heart disease. Biochem Soc Trans 24: 785–789, 1996

    PubMed  Google Scholar 

  28. Bhathena SJ, Velasquez MT: Beneficial role of dietary phytoestrogens in obesity and diabetes. Am J Clin Nutr 76: 1191–201, 2002

    PubMed  Google Scholar 

  29. Jacobs MN, Lewis DF: Steroid hormone receptors and dietary lig-ands: A selected review. Proc Nutr Soc 61: 105–122, 2002

    PubMed  Google Scholar 

  30. Hollman PC, van Trijp JM, Buysman MN, van der Gaag MS, Mengelers MJ, de Vries H, Katan MB: Relative bioavailability of the antioxidant flavonoid quercetin from various foods in man. FEBS Lett 418: 152–156, 1997

    PubMed  Google Scholar 

  31. Howes MJ, Perry NS, Houghton PJ: Plants with traditional uses and activities, relevant to the management of Alzheimer's disease and other cognitive disorders. Phytother Res 17: 1–18, 2003

    PubMed  Google Scholar 

  32. Arliss RM, Biermann CA: Do soy isoflavones lower cholesterol, inhibit atherosclerosis, and play a role in cancer prevention? Holist Nurs Pract 16: 40–48, 2002

    Google Scholar 

  33. Castle EP, Thrashe JB: The role of soy phytoestrogens in prostate cancer. Urol Clin North Am 29: 71–81, 2002

    PubMed  Google Scholar 

  34. Bright JJ, Sriram S: TGF-beta inhibits IL-12-induced activation of JAK-STAT pathway in T lymphocytes. J Immunol 161: 1772–1777, 1998

    PubMed  Google Scholar 

  35. Bright JJ, Kerr LD, Sriram S: TGF-beta inhibits IL-2-induced tyrosine phosphorylation and activation of JAK1 and STAT5 in T lymphocytes. J Immunol 159: 175–183, 1997

    PubMed  Google Scholar 

  36. Mishell BB, Shiigi SM: Selected Methods in Cellular Immunology. San Francisco, CA, Freeman, 1980

    Google Scholar 

  37. Du C, Bright JJ, Sriram S: Inhibition of CD40 signaling pathway by tyrphostin A1 reduces secretion of IL-12 in macrophage Th1 cell development and experimental allergic encephalomyelitis in SJL/J mice. J Neuroimmunol 114: 69–79, 2001

    PubMed  Google Scholar 

  38. Walker WS, Gatewood J, Olivas E, Askew D, Havenith C: Mouse microglial cell lines differing in constitutive and interferon-gamma-inducible antigen-presenting activities for naive and memory CD4 +and CD8 +T cells. J Neuroimmunol 63: 163–174, 1995

    PubMed  Google Scholar 

  39. Bright JJ, Musuro BF, Du C, Sriram S: Expression of IL-12 in CNS and lymphoid organs of mice with experimental allergic en-cephalomyelitis. J Neuroimmunol 82: 22–30, 1998

    PubMed  Google Scholar 

  40. Bright JJ, Rodriguez M, Sriram S: Differential influence of interleukin-12 in the pathogenesis of autoimmune and virus-induced CNS demyelination. J Virol 73: 1637–1639, 1999

    PubMed  Google Scholar 

  41. Bright JJ, Du C, Coon M, Sriram S, Klaus SJ: Prevention of exper-imental allergic encephalomyelitis via inhibition of IL-12 signaling and IL-12-mediated Th1 differentiation: An effect of the novel anti-inflammatory drug lisofylline. J Immunol 161: 7015–7022, 1998

    PubMed  Google Scholar 

  42. Bright JJ, Du C, Sriram S: Tyrphostin B42 inhibits IL-12-induced ty-rosine phosphorylation and activation of Janus kinase-2 and prevents experimental allergic encephalomyelitis. J Immunol 162: 6255–6262, 1999

    PubMed  Google Scholar 

  43. Bright JJ, Natarajan C, Muthian G, Barak Y, Evans RM: Peroxisome proliferator-activated receptor-gamma-deficient heterozygous mice develop an exacerbated neural antigen-induced Th1 response and experimental allergic encephalomyelitis. J Immunol 171: 5743–5750, 2003

    PubMed  Google Scholar 

  44. Hendriks JJ, de Vries HE, van der Pol SM, van den Berg TK, van Tol EA, Dijkstra CD: Flavonoids inhibit myelin phagocytosis by macrophages: A structure-activity relationship study. Biochem Pharmacol 65: 877–885, 2003

    PubMed  Google Scholar 

  45. Shen SC, Lee WR, Lin HY, Huang HC, Ko CH, Yang L, Chen YC: In vitro and in vivo inhibitory activities of rutin, wogonin, and quercetin on lipopolysaccharide-induced nitric oxide and prostaglandin E(2) production. Eur J Pharmacol 446: 187–194, 2002

    PubMed  Google Scholar 

  46. Guardia T, Rotelli AE, Juarez AO, Pelzer LE: Anti-inflammatory properties of plant flavonoids. Effects of rutin, quercetin and hesperidin on adjuvant arthritis in rat. Farmaco 56: 683–687, 2001

    PubMed  Google Scholar 

  47. Sobottka AM, Werner W, Blaschke G, Kiefer W, Nowe U, Dannhardt G, Schapoval P, Schenkel EE, Scriba GK: Effect of flavonol derivatives on the carrageenin-induced paw edema in the rat and inhibition of cyclooxygenase-1 and 5-lipoxygenase in vitro. Arch Pharm 333: 205–210, 2000

    Google Scholar 

  48. Muraoka K, Shimizu K, Sun X, Tani T, Izumi R, Miwa K, Yamamoto K: Flavonoids exert diverse inhibitory effects on the activation of NF-kappaB. Transplant Proc 34: 1335–1340, 2002

    PubMed  Google Scholar 

  49. Peet GW, Li J: IkappaB kinases alpha and beta show a random sequential kinetic mechanism and are inhibited by staurosporine and quercetin. J Biol Chem 274: 32655–32661, 1999

    PubMed  Google Scholar 

  50. Zhang G, Ghosh S: Molecular mechanisms of NF-kappaB activation induced by bacterial lipopolysaccharide through Toll-like receptors. J Endotoxin Res 6: 453–457, 2000

    PubMed  Google Scholar 

  51. Murphy TL, Cleveland MG, Kulesza P, Magram J, Murphy KM: Regulation of interleukin 12 p40 expression through an NF-kappaB half-site. Mol Cell Biol 15: 5258–5267, 1995

    PubMed  Google Scholar 

  52. You KM, Son KH, Chang HW, Kang SS, Kim HP: Vitexicarpin, a flavonoid from the fruits of Vitex rotundifolia, inhibits mouse lym-phocyte proliferation and growth of cell lines in vitro. Planta Med 64: 546–550, 1998

    PubMed  Google Scholar 

  53. Okamoto I, Iwaki K, Koya-Miyata S, Tanimoto T, Kohno K, Ikeda M, Kurimoto M: The flavonoid Kaempferol suppresses the graft-versus-host reaction by inhibiting type 1 cytokine production and CD8 +T cell engraftment. Clin Immunol 103: 132–144, 2002

    PubMed  Google Scholar 

  54. Gately MK, Desai BB, Wolitzky AG, Quinn PM, Dwyer CM, Podlaski FJ, Familletti PC, Sinigaglia F, Chizonnite R, Guble U: Regulation of human lymphocyte proliferation by a het-erodimeric cytokine, IL-12 (cytotoxic lymphocyte maturation factor). J Immunol 147: 874–882, 1991

    PubMed  Google Scholar 

  55. Bertagnolli MM, Lin BY, Young D, Herrmann SH: IL-12 augments antigen-dependent proliferation of activated T lymphocytes. J Immunol 149: 3778–3783, 1992

    PubMed  Google Scholar 

  56. Yanagida T, Kato T, Igarashi O, Inoue T, Nariuchi H: Second signal activity of IL-12 on the proliferation and IL-2R expression of T helper cell-1 clone. J Immunol 152: 4919–4928, 1994

    PubMed  Google Scholar 

  57. Nguyen T, Wang R, Russell JH: IL-12 enhances IL-2 function by inducing CD25 expression through a p38 mitogen-activated protein kinase pathway. Eur J Immunol 30: 1445–1452, 2000

    PubMed  Google Scholar 

  58. Kennedy MK, Picha KS, Shanebeck KD, Anderson DM, Grabstein KH: Interleukin-12 regulates the proliferation of Th1, but not Th2 or Th0, clones. Eur J Immunol 24: 2271–2278, 1994

    PubMed  Google Scholar 

  59. Jacobson NG, Szabo SJ, Weber-Nordt RM, Zhong Z, Schreiber RD, Darnell JE, Jr, Murphy KM: Interleukin-12 signaling in Th1 cells involves tyrosine phosphorylation of STAT 3 and STAT 4. J Exp Med 181: 1755–1762, 1995

    PubMed  Google Scholar 

  60. Bacon CM, Petricoin EM, Ortaldo JR, Rees RC, Larner AC, Johnston JA, O'shea JJ: Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes. Proc Natl Acad Sci USA 92: 7307–7311, 1995

    PubMed  Google Scholar 

  61. Bito T, Roy S, Sen CK, Shirakawa T, Gotoh A, Ueda M, Ichihashi M, Packer L: Flavonoids differentially regulate IFN gamma-induced ICAM-1 expression in human keratinocytes: Molecular mechanisms of action. FEBS Lett 520: 145–152, 2002

    PubMed  Google Scholar 

  62. Thierfelder WE, van Deursen JM, Yamamoto K, Tripp RA, Sarawar SR, Carson RT, Sangster MY, Vignali DA, Doherty PC, Grosveld GC, Ihle JN: Requirement for STAT4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382: 171–174, 1996

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Neurology and Pharmacology, Vanderbilt, University Medical Center, Nashville, Tennessee

    Gladson Muthian & John J. Bright

Authors
  1. Gladson Muthian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John J. Bright
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Muthian, G., Bright, J.J. Quercetin, a Flavonoid Phytoestrogen, Ameliorates Experimental Allergic Encephalomyelitis by Blocking IL-12 Signaling Through JAK-STAT Pathway in T Lymphocyte. J Clin Immunol 24, 542–552 (2004). https://doi.org/10.1023/B:JOCI.0000040925.55682.a5

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:JOCI.0000040925.55682.a5

search

Navigation