Journal of Clinical Immunology

, Volume 28, Issue 5, pp 558–570 | Cite as

15-Deoxy-Δ12,14-Prostaglandin J2 and Curcumin Modulate the Expression of Toll-like Receptors 4 and 9 in Autoimmune T Lymphocyte




Experimental allergic encephalomyelitis (EAE) is a T cell-mediated autoimmune disease model for multiple sclerosis (MS). We have shown earlier that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and curcumin ameliorate EAE by modulating inflammatory signaling pathways in T lymphocytes. Toll-like receptors (TLRs), expressed primarily in innate immune cells, play critical roles in the pathogenesis of EAE. T lymphocytes also express TLRs and function as costimulatory receptors to upregulate proliferation and cytokine production in response to specific agonists.


In this study, we show that naïve CD4+ and CD8+ T cells express detectable levels of TLR4 and TLR9 and that increase after the induction of EAE in SJL/J and C57BL/6 mice by immunization with PLPp139–151 and MOGp35–55 antigen, respectively. It is interesting to note that in vivo treatment with 15d-PGJ2 or curcumin results in a significant decrease in TLR4 and TLR9 expression in CD4+ and CD8+ T cells in association with the amelioration of EAE.


Although the exact mechanisms are not known, the modulation of TLR expression in T lymphocytes by 15d-PGJ2 and curcumin suggests new therapeutic targets in the treatment of T cell-mediated autoimmune diseases.


Autoimmune disease EAE/MS inflammation Th1 cell toll-like receptor 



multiple sclerosis


experimental allergic encephalomyelitis


myelin basic protein


myelin oligodendrocyte glycoprotein


proteolipid protein


central nervous system


peroxisome proliferator-activated receptor gamma


15-deoxy-Δ12,14-prostaglandin J2




antigen-presenting cells


T helper 1


pathogen-associated molecular patterns




interleukin 1 receptor-associated kinase


tumor necrosis factor receptor-associated factor


nuclear factor kappa B


activated protein 1


mitogen-activated protein kinase

MHC, major histocompatibility complex

PE, phycoerythrin


fluorescence isothiocyanate


fetal bovine serum


bovine serum albumin


complete Freund’s adjuvant




mean clinical score



This work was supported in part by the National Institutes of Health, grant R01 NS42257-01A1 (to J.J.B).


  1. 1.
    Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med 2000;343:938–52.PubMedCrossRefGoogle Scholar
  2. 2.
    Bitsch A, Bruck W. Differentiation of multiple sclerosis subtypes: implications for treatment. CNS Drugs 2002;6:405–18.CrossRefGoogle Scholar
  3. 3.
    Wingerchuk DM, Lucchinetti CF, Noseworthy JH. Multiple sclerosis: current pathophysiological concepts. Lab Invest 2001;81:263–81.PubMedGoogle Scholar
  4. 4.
    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 2002;25:491–505.PubMedCrossRefGoogle Scholar
  5. 5.
    Franklin RJ. Why does remyelination fail in multiple sclerosis? Nat Rev Neurosci 2002;3:705–14.PubMedCrossRefGoogle Scholar
  6. 6.
    Coleman MP, Perry VH. Axon pathology in neurological disease: a neglected therapeutic target. Trends Neurosci 2002;25:532–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Gold R, Hartung HP, Toyka KV. Animals model for auto immune demyelinating disorders of the nervous system. Mol Med Today 2000;6:88–91.PubMedCrossRefGoogle Scholar
  8. 8.
    Bright JJ, Sriram S. Immunotherapy of inflammatory demyelinating diseases of the central nervous system. Immunol Res 2001;23:245–52.PubMedCrossRefGoogle Scholar
  9. 9.
    Muthian G, Bright JJ. Quercetin ameliorates experimental allergic encephalomyelitis by blocking IL-12 signaling through JAK–STAT pathway in T lymphocyte. J Clin Immunol 2003;24:541–51.Google Scholar
  10. 10.
    Raikwar HP, Muthian G, Rajasingh J, Johnson C, Bright JJ. PPARg antagonists exacerbate neural antigen-specific Th1 response and experimental allergic encephalomyelitis. J Neuroimmunol 2005;167:99–107.PubMedCrossRefGoogle Scholar
  11. 11.
    Muthian G, Raikwar HP, Johnson C, Rajasingh J, Kalgutkar AS, Marnett LJ, Bright JJ. COX-2 inhibitors modulate IL-12 signaling through JAK–STAT pathway leading to Th1 response in experimental allergic encephalomyelitis. J Clin Immunol 2006;26:73–85.PubMedCrossRefGoogle Scholar
  12. 12.
    Muthian G, Raikwar HP, Rajasingh J, Bright JJ. 1, 25 Dihydroxyvitamin-D3 modulates JAK–STAT pathway in IL-12/IFNg axis leading to Th1 response in experimental allergic encephalomyelitis. J Neurosci Res 2006;83:1299–309.PubMedCrossRefGoogle Scholar
  13. 13.
    Evans RM. The steroid and thyroid hormone receptor superfamily. Science 1998;240:889–95.CrossRefGoogle Scholar
  14. 14.
    Blumberg B, Evans RM. Orphan nuclear receptors: new ligands and new possibilities. Genes Dev 1998;12:3149–55.PubMedCrossRefGoogle Scholar
  15. 15.
    Mukherjee R, Jow L, Croston GE, Paterniti JR. Identification, characterization and tissue distribution of human peroxisome proliferator activated receptor isoforms 1 and 2 and activation with retinoid x receptor agonists and antagonists. J Biol Chem 1997;272:8071–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Elbrecht A, Chen Y, Cullinan CA, Hayes N, Leibowitz M, Moller DE, Berger J. Molecular cloning, expression and characterization of human peroxisome proliferator activated receptors gamma 1 and gamma 2. Biochem Biophys Res Commun 1996;224:431–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman B, Evans RM. 15-Deoxy-12, 14 prostaglandin J2 a ligand for the adipocyte determination factor PPAR gamma. Cell 1995;83:803–12.PubMedCrossRefGoogle Scholar
  18. 18.
    Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPARg). J Biol Chem 1995;270:12953–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-g is a negative regulator of macrophage activation. Nature 1998;391:79–82.PubMedCrossRefGoogle Scholar
  20. 20.
    Jiang C, Ting AT, Seed B. PPARg agonists inhibit production of monocyte inflammatory cytokine. Nature 1998;391:82–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Kawahito Y, Kondo M, Tsubouchi Y, Hashiramoto A, Bishop-Bailey D, Inoue K, Kohno M, Yamada R, Hla T, Sano H. 15-deoxy D12,14 prostaglandin J2 induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats. J Clin Invest 2000;106:189–97.PubMedCrossRefGoogle Scholar
  22. 22.
    Neve BP, Fruchart JC, Staels B. Role of the peroxisome proliferator-activated receptors (PPAR) in atherosclerosis. Biochem Pharmacol 2000;60:1245–50.PubMedCrossRefGoogle Scholar
  23. 23.
    Niino M, Iwabuchi K, Kikuchi S, Ato M, Morohashi T, Ogata A, Tashiro K, Onoé K. Amelioration of experimental autoimmune encephalomyelitis in C57BL/6 mice by an agonist of PPARg. J. Neuroimmunol 2001;116:40–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Diab A, Deng C, Smith JD, Hussain RZ, Phanavanh B, Lovett-Racke AB, Drew PD, Racke MK. Peroxisome proliferator-activated receptor-gamma agonist 15-deoxy D12,14 prostaglandin J2 ameliorates experimental autoimmune encephalomyelitis. J Immunol 2002;168:2508–15.PubMedGoogle Scholar
  25. 25.
    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 2002;3:59–70.PubMedCrossRefGoogle Scholar
  26. 26.
    Feinstein DL, Galea E, Gavrilyuk V, Brosnan CF, Whitacre CC, Dumitrescu-Ozimek L, Landreth GE, Pershadsingh HA, Weinberg G, Heneka MT. Peroxisome proliferator activated receptor-gamma agonists prevent experimental autoimmune encephalomyelitis. Ann Neurol 2002;51:694–702.PubMedCrossRefGoogle Scholar
  27. 27.
    Schmidt S, Moric E, Schmidt M, Sastre M, Feinstein DL, Heneka MT. Anti-inflammatory and antiproliferative actions of PPAR-gamma agonists on T lymphocytes derived from MS patients. J Leukoc Biol 2004;75:478–85.PubMedCrossRefGoogle Scholar
  28. 28.
    Natarajan C, Muthian G, Barak Y, Evans RM, Bright JJ. Peroxisome proliferator-activated receptor-gamma deficient heterozygous mice develop an exacerbated neural antigen-induced Th1 response and experimental allergic encephalomyelitis. J Immunol 2003;171:5743–50.PubMedGoogle Scholar
  29. 29.
    Surh Y. Molecular mechanisms of chemopreventive effects of selected dietary and medicinal phenolic substances. Mutat Res 1999;428:305–27.PubMedGoogle Scholar
  30. 30.
    Ammon HP, Safayhi H, Mack T, Sabieraj J. Mechanism of antiinflammatory actions of curcumine and boswellic acids. J Ethnopharmacol 1993;38:113–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Arora RB, Kapoor V, Basu N, Jain AP. Anti-inflammatory studies on Curcuma longa (turmeric). Indian J Med Res 1971;59:1289–95.PubMedGoogle Scholar
  32. 32.
    Chandra D, Gupta SS. Anti-inflammatory and anti-arthritic activity of volatile oil of Curcuma longa. Indian J Med Res 1972;60:138–42.PubMedGoogle Scholar
  33. 33.
    Ghatak N, Basu N. Sodium curcuminate as an effective anti-inflammatory agent. Indian J Exp Biol 1972;10:235–6.PubMedGoogle Scholar
  34. 34.
    Mukhopadhyay A, Basu N, Ghatak N, Gujral PK. Anti-inflammatory and irritant activities of curcumin analogues in rats. Agents Actions 1982;12:508–15.PubMedCrossRefGoogle Scholar
  35. 35.
    Srimal RC, Dhawan BN. Pharmacology of diferuloyl methane (curcumin), a non-steroidal anti-inflammatory agent. J Pharm Pharmacol 1973;25:447–52.PubMedGoogle Scholar
  36. 36.
    Natarajan C, Bright JJ. Curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through Janus kinase-STAT pathway in T lymphocytes. J Immunol 2002;168:6506–13.PubMedGoogle Scholar
  37. 37.
    Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996;86:973–83.PubMedCrossRefGoogle Scholar
  38. 38.
    Anderson KV. Toll signaling pathways in the innate immune response. Curr Opin Immunol 2000;12:13–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Schwandner RR, Dziarski H, Wesche M, Rothe CJ, Kirschning CJ. Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by Toll-like receptor 2. J Biol Chem 1999;274:17406–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Aliprantis AO, Yang RB, Mark MR, Suggett S, Devaux B, Radolf JD, Klimpel GR, Godowski P, Zychlinsky A. Cell activation and apoptosis by bacterial lipoproteins through Toll-like receptor-2. Science 1999;285:736–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Alexopoulou L, Holt AC, Medzhitov R, Flavell A. Recognition of double-stranded RNA and activation of NF-kB by Toll-like receptor 3. Nature 2001;413:732–8.PubMedCrossRefGoogle Scholar
  42. 42.
    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 1998;282:2085–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 2001;410:1099–103.PubMedCrossRefGoogle Scholar
  44. 44.
    Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K, Akira S. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 2002;3:196–200.PubMedCrossRefGoogle Scholar
  45. 45.
    Jurk M, Heil F, Vollmer J, Schetter C, Krieg AM, Wagner H, Lipford G, Bauer S. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol 2002;3:196–200.CrossRefGoogle Scholar
  46. 46.
    Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 2004;303:1526–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Diebold SS, Kaisho T, Hemmi H, Akira S, Sousa CR. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 2004;303:1529–31.PubMedCrossRefGoogle Scholar
  48. 48.
    Hemmi HO, Takeuchi T, Kawai T, Kaisho Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, Akira S. A Toll-like receptor recognizes bacterial DNA. Nature 2000;408:740–5.PubMedCrossRefGoogle Scholar
  49. 49.
    Underhill DM. Toll-like receptors: networking for success. Eur J Immunol 2003;33:1767–75.PubMedCrossRefGoogle Scholar
  50. 50.
    Barton GM, Medzhitov R. Toll-like receptor signaling pathways. Science 2003;300:1524–5.PubMedCrossRefGoogle Scholar
  51. 51.
    Medzhitov R, Preston-Hurlburt P, Kopp E, Stadlen A, Chen C, Ghosh S Jr, Janeway CA. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell 1998;2:253–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Muzio M, Ni J, Feng P, Dixit VM. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 1997;278:1612–5.PubMedCrossRefGoogle Scholar
  53. 53.
    Kawai T, Adachi O, Ogawa T, Takeda K, Akira S. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 1997;11:115–22.CrossRefGoogle Scholar
  54. 54.
    Adachi O, Kawai T, Takeda K, Matsumoto M, Tsutsui H, Sakagami M, Nakanishi K, Akira S. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 1998;9:143–50.PubMedCrossRefGoogle Scholar
  55. 55.
    Takeuchi O, Takeda K, Hoshino K, Adachi O, Ogawa T, Akira S. Cellular responses to bacterial cell wall components are mediated through MyD88-dependent signaling cascades. Int Immunol 2000;2:113–7.CrossRefGoogle Scholar
  56. 56.
    Häcker H, Vabulas RM, Takeuchi O, Hoshino K, Akira S, Wagner H. Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF) 6. J Exp Med 2000;192:595–600.PubMedCrossRefGoogle Scholar
  57. 57.
    Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B, Giese T, Endres S, Hartmann G. Quantitative expression of toll-like receptor 1–10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol 2002;168:4531–7.PubMedGoogle Scholar
  58. 58.
    Zarember KA, Godowski PJ. Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol 2002;168:554–61.PubMedGoogle Scholar
  59. 59.
    Kaisho T, Akira S. Dendritic cell function in Toll-like receptor and MyD88 knockout mice. Trends Immunol 2001;22:78–83.PubMedCrossRefGoogle Scholar
  60. 60.
    Bsibsi M, Ravid R, Gveric D, van Noort JM. Broad expression of Toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol 2002;61:1013–21.PubMedGoogle Scholar
  61. 61.
    Zekki H, Feinstein DL, Rivest S. The clinical course of experimental autoimmune encephalomyelitis is associated with a profound and sustained transcriptional activation of the genes encoding toll-like receptor 2 and CD14 in the mouse CNS. Brain Pathol 2002;12:308–19.PubMedGoogle Scholar
  62. 62.
    Kerfoot SM, Long EM, Hickey MJ, Andonegui G, Lapointe GB, Zanardo RC, Bonder C, James WG, Robbins SM, Kubes P. TLR4 contributes to disease-inducing mechanisms resulting in central nervous system autoimmune disease. J Immunol 2004;173:7070–7.PubMedGoogle Scholar
  63. 63.
    Racke MK, Hu W, Lovett-Racke AE. PTX cruiser: driving autoimmunity via TLR4. Trends Immunol 2005;26:289–91.PubMedCrossRefGoogle Scholar
  64. 64.
    Hansen BS, Hussain RZ, Lovett-Racke AE, Thomas JA, Racke MK. Multiple toll-like receptor agonists act as potent adjuvants in the induction of autoimmunity. J Neuroimmunol 2006;172:94–103.PubMedCrossRefGoogle Scholar
  65. 65.
    Prinz M, Garbe F, Schmidt H, Mildner A, Gutcher I, Wolter K, Piesche M, Schroers R, Weiss E, Kirschning CJ, Rochford CD, Bruck W, Becher B. Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis. J Clin Invest 2006;116:456–64.PubMedCrossRefGoogle Scholar
  66. 66.
    Wolf NA, Amouzegar TK, Swanborg RH. Synergistic interaction between Toll-like receptor agonists is required for induction of experimental autoimmune encephalomyelitis in Lewis rats. J Neuroimmunol 2007;185:115–22.PubMedCrossRefGoogle Scholar
  67. 67.
    Komai-Koma M, Jones L, Ogg GS, Xu D, Liew FY. TLR2 is expressed on activated T cells as a costimulatory receptor. Proc Natl Acad Sci U S A 2004;101:3029–34.PubMedCrossRefGoogle Scholar
  68. 68.
    Caron G, Duluc D, Fremaux I, Jeannin P, David C, Gascan H, Delneste Y. Direct stimulation of human T cells via TLR5 and TLR7/8: flagellin and R-848 up-regulate proliferation and IFN-g production by memory CD4+ T cells. J Immunol 2005;175:1551–7.PubMedGoogle Scholar
  69. 69.
    Touil T, Fitzgerald D, Zhang GX, Rostami A, Gran B. TLR3 stimulation suppresses experimental autoimmune encephalomyelitis by inducing endogenous IFN-beta. J Immunol 2006;177:7505–9.PubMedGoogle Scholar
  70. 70.
    Ogawa S, Lozach J, Benner C, Pascual G, Tangirala RK, Westin S, Hoffmann A, Subramaniam S, David M, Rosenfeld MG, Glass CK. Molecular determinants of cross-talk between nuclear receptors and toll-like receptors. Cell 2005;122:707–21.PubMedCrossRefGoogle Scholar
  71. 71.
    Appel S, Mirakaj V, Bringmann A, Weck MM, Grunebach F, Brossart P. PPAR-gamma agonists inhibit toll-like receptor-mediated activation of dendritic cells via the MAP kinase and NF-kappaB pathways. Blood 2005;106:3888–94.PubMedCrossRefGoogle Scholar
  72. 72.
    Phulwani NK, Feinstein DL, Gavrilyuk V, Akar C, Kielian T. 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) and ciglitazone modulate Staphylococcus aureus-dependent astrocyte activation primarily through a PPAR-gamma-independent pathway. J Neurochem 2006;99:1389–402.PubMedCrossRefGoogle Scholar
  73. 73.
    Chowdhury P, Sacks SH, Sheerin NS. Toll-like receptors TLR2 and TLR4 initiate the innate immune response of the renal tubular epithelium to bacterial products. Clin Exp Immunol 2006;145:346–56.PubMedCrossRefGoogle Scholar
  74. 74.
    Youn HS, Saitoh SI, Miyake K, Hwang DH. Inhibition of homodimerization of Toll-like receptor 4 by curcumin. Biochem Pharmacol 2006;72:62–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Kato S, Yuzawa Y, Tsuboi N, Maruyama S, Morita Y, Matsuguchi T, Matsuo S. Endotoxin-induced chemokine expression in murine peritoneal mesothelial cells: the role of toll-like receptor 4. J Am Soc Nephrol 2004;15:1289–99.PubMedGoogle Scholar
  76. 76.
    Eun CS, Han DS, Lee SH, Paik CH, Chung YW, Lee J, Hahm JS. Attenuation of colonic inflammation by PPARg in intestinal epithelial cells: effect on Toll-like receptor pathway. Dig Dis Sci 2006;51:693–7.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Neuroscience Research LaboratoryMethodist Research Institute at Clarian HealthIndianapolisUSA
  2. 2.Department of MedicineIndiana University School of MedicineIndianapolisUSA

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