Mast Cells, T Cells, and Inhibition by Luteolin: Implications for the Pathogenesis and Treatment of Multiple Sclerosis

  • Theoharis C. Theoharides
  • Duraisamy Kempuraj
  • Betina P. Iliopoulou
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 601)


Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) mainly mediated by Th1, but recent evidence indicates that Th2 T cells, mostly associated with allergic reactions, are also involved. Mast cells are involved in allergic and inflammatory reactions because they are located perivascularly and secrete numerous pro-inflammatory cytokines. Brain mast cells are critically placed around the blood–brain barrier (BBB) and can disrupt it, a finding preceding any clinical or pathological signs of MS. Moreover, mast cells are often found close to MS plaques, and the main MS antigen, myelin basic protein (MBP), can activate human cultured mast cells to release IL-8, TNF-α , tryptase, and histamine. Mast cells could also contribute to T cell activation since addition of mast cells to anti-CD3/anti-CD28 activated T cells increases T cell activation over 30-fold. This effect requires cell-to-cell contact and TNF, but not histamine or tryptase. Pretreatment with the flavone luteolin totally blocks mast cell stimulation and T cell activation. Mast cells could constitute a new unique therapeutic target for MS.


Multiple Sclerosis Mast Cell Myelin Basic Protein Human Mast Cell Central Nervous System Inflammation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Aktas, O., Prozorovski, T., Smorodchenko, A., Savaskan, N.E., Lauster, R., Kloetzel, P.M., Infante-Duarte, C., Brocke, S. and Zipp, F. (2004) Green tea epigallocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J. Immunol. 173, 5794–5800.PubMedGoogle Scholar
  2. Bomprezzi, R., Ringner, M., Kim, S., Bittner, M.L., Khan, J., Chen, Y., Elkahloun, A., Yu, A., Bielekova, B., Meltzer, P.S., Martin, R., McFarland, H.F. and Trent, J.M. (2003) Gene expression profile in multiple sclerosis patients and healthy controls: identifying pathways relevant to disease. Hum. Mol. Genet. 12,2191–2199.CrossRefPubMedGoogle Scholar
  3. Brill, A., Baram, D., Sela, U., Salamon, P., Mekori, Y.A. and Hershkoviz, R. (2004) Induction of mast cell interactions with blood vessel wall components by direct contact with intact T cells or T cell membranes in vitro. Clin. Exp. Allergy 34, 1725–1731.CrossRefPubMedGoogle Scholar
  4. Brown, M.A., Tanzola, M. and Robbie-Ryan. M. (2002) Mechanisms underlying mast cell influence on EAE disease course. Mol. Immunol. 38:1373–1378.CrossRefPubMedGoogle Scholar
  5. Dery, O., Corvera, C.U., Steinhoff, M. and Bunnett, N.W. (1998) Proteinase-activated receptors: novel mechanisms of signaling by serine proteases. Am. J. Physiol. 274, C1429–C1452.PubMedGoogle Scholar
  6. Dietsch, G.N. and Hinrichs, D.J, (1991) Mast cell proteases liberate stable encephalitogenic fragments from intact myelin. Cell. Immunol. 135, 541–548.CrossRefPubMedGoogle Scholar
  7. Duthie, S.J., Johnson, W. and Dobson, V.L. (1997) The effect of dietary flavonoids on DNA damage (strand breaks and oxidised pyrimidines) and growth in human cells. Mutat. Res. 390, 141–151.PubMedGoogle Scholar
  8. Esposito, P., Chandler, N., Kandere-Grzybowska, K., Basu, S., Jacobson, S., Connolly, R., Tutor, D. and Theoharides, T.C. (2002) Corticotropin-releasing hormone (CRH) and brain mast cells regulate blood-brain-barrier permeability induced by acute stress. J. Pharmacol. Exp. Ther. 303, 1061–1066.CrossRefPubMedGoogle Scholar
  9. Foreman, J.C. (1984) Mast cells and the actions of flavonoids. J. Allergy Clin. Immunol. 73, 769–774.CrossRefPubMedGoogle Scholar
  10. Galli, S.J. (1990) New insights into “the riddle of the mast cells”: microenvironmental regulation of mast cell development and phenotypic heterogeneity. Lab. Invest. 62, 5–33.PubMedGoogle Scholar
  11. Galli, S.J., Nakae, S. and Tsai, M. (2005) Mast cells in the development of adaptive immune responses. Nat. Immunol. 6, 135–142.CrossRefPubMedGoogle Scholar
  12. Goldn, R. (2007) Towards individualized multiple sclerosis therapy. Lancet Neurol. 4, 693–694.CrossRefGoogle Scholar
  13. Gregory, G.D., Raju, S.S., Winandy, S. and Brown. M.A.(2006) Mast cell IL-4 expression is regulated by Ikaros and influences encephalitogenic Th1 responses in EAE. J. Clin. Invest. 116, 1327–1336.CrossRefPubMedGoogle Scholar
  14. Halliwell, B. (2001) Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drugs Aging 18, 685–716.CrossRefPubMedGoogle Scholar
  15. Hendriks, J.J., Alblas, J., van der Pol, S.M., van Tol, E.A., Dijkstra, C.D. and de Vries, H.E. (2004) Flavonoids influence monocytic GTPase activity and are protective in experimental allergic encephalitis. J. Exp. Med. 200, 1667–1672.CrossRefPubMedGoogle Scholar
  16. Herrmann, K. (1976) Flavonols and flavones in food plants. J. Food Technol. 11, 433–448.CrossRefGoogle Scholar
  17. Hirano, T., Higa, S., Arimitsu, J., Naka, T., Ogata, A., Shima, Y., Fujimoto, M., Yamadori , T., Ohkawara, T., Kuwabara, Y., Kawai, M., Matsuda, H.,Yoshikawa M., Maezaki, N., Tanaka, T., Kawase, I. and Tanaka, T. (2006) Luteolin, a flavonoid, inhibits AP-1 activation by basophils. Biochem. Biophys. Res. Commun. 340, 1–7.CrossRefPubMedGoogle Scholar
  18. Ibrahim, M.Z.M., Reder, A.T., Lawand, R., Takash, W. and Sallouh-Khatib, S. (1996) The mast cells of the multiple sclerosis brain. J. Neuroimmunol. 70, 131–138.CrossRefPubMedGoogle Scholar
  19. Johnson, D., Seeldrayers, P.A. and Weiner, H.L. (1988) The role of mast cells in demyelination. 1. Myelin proteins are degraded by mast cell proteases and myelin basic protein and P2 can stimulate mast cell degranulation. Brain Res. 444, 195–198.CrossRefPubMedGoogle Scholar
  20. Jutel, M., Watanabe, T., Klunker, S., Akdis, M., Thomet, O.A.R., Malolepszy, J., Zak-Nejmark, T., Koga, R., Kobayashi, T., Blaser, K. and Akdis, C.A. (2001) Histamine regulates T cell and antibody responses by differential expression of H1 and H2 receptors. Nature 413, 420–425.CrossRefPubMedGoogle Scholar
  21. Kandere-Grzybowska, K., Kempuraj, D., Cao, J., Cetrulo, C.L. and Theoharides, T.C. (2006) Regulation of IL-1-induced selective IL-6 release from human mast cells and inhibition by quercetin. Br. J. Pharmacol.148, 208–215.CrossRefPubMedGoogle Scholar
  22. Kempuraj, D., Madhappan, B., Christodoulou, S., Boucher, W., Cao, J., Papadopoulou, N., Cetrulo, C.L. and Theoharides, T.C. (2005) Flavonols inhibit proinflammatory mediator release, intracellular calcium ion levels and protein kinase C theta phosphorylation in human mast cells. Br. J. Pharmacol. 145, 934–944.CrossRefPubMedGoogle Scholar
  23. Kimata, M., Inagaki, N. and Nagai, H. (2000) Effects of luteolin and other flavonoids on IgE-mediated allergic reactions. Planta Med. 66, 25–29.CrossRefPubMedGoogle Scholar
  24. Krüger, P.G. (2001) Mast cells and multiple sclerosis: a quantitative analysis. Neuropathol Appl. Neurobiol. 27, 275–280.CrossRefPubMedGoogle Scholar
  25. Lassmann, H. and Ransohoff, R.M. (2004) The CD4-Th1 model for multiple sclerosis: a crucial re-appraisal. Trends Immunol. 25, 132–137.CrossRefPubMedGoogle Scholar
  26. Lock, C., Hermans, G., Pedotti, R., Brendolan, A., Schadt, E., Garren, H., Langer-Gould, A., Strober, S., Cannella, B., Allard, J., Klonowski, P., Austin, A., Lad, N., Kaminski, N., Galli, S.J., Oksenberg, J.R., Raine, C.S., Heller, R. and Steinman, L. (2002) Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 8, 500–508.CrossRefPubMedGoogle Scholar
  27. Lu, F., Selak, M., O’Connor, J., Croul, S., Lorenzana, C., Butunoi, C. and Kalman, B. (2000) Oxidative damage to mitochondrial DNA and activity of mitochondrial enzymes in chronic active lesions of multiple sclerosis. J. Neurol. Sci. 177, 95–103.CrossRefPubMedGoogle Scholar
  28. Macey, M.G., Hou, L., Milne, T., Parameswaren, V., Howe, D., Cavenagh, J.D., Howells, G.L. and Newland, A.C. (1998) A CD4+ proliferation of large granular lymphocytes expresses the protease activated receptor-1. Br. J. Haematol. 101, 78–81.CrossRefPubMedGoogle Scholar
  29. Malamud, V., Vaaknin, A., Abramsky, O., Mor, M., Burgess, L.E., Ben-Yehudah, A. and Lorberboum-Galski, H. (2003) Tryptase activates peripheral blood mononuclear cells causing the synthesis and release of TNF-alpha, IL-6 and IL-1 beta: possible relevance to multiple sclerosis. J. Neuroimmunol. 138, 115–122.CrossRefPubMedGoogle Scholar
  30. Martino, G., Furlan R. and Poliani, P.L. (2000) [The pathogenic role of inflammation in multiple sclerosis]. Rev. Neurol. 30, 1213–1217.PubMedGoogle Scholar
  31. Middleton, E., Jr. (1998) Effect of plant flavonoids on immune and inflammatory cell function. Adv. Exp. Med. Biol. 439, 175–182.PubMedGoogle Scholar
  32. Middleton, E., Jr., Kandaswami, C. and Theoharides, T.C. (2000) The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease and cancer. Pharmacol. Rev. 52, 673–751.PubMedGoogle Scholar
  33. Minagar, A. and Alexander, J.S. (2003) Blood-brain barrier disruption in multiple sclerosis. Mult. Scler. 9, 540–549.CrossRefPubMedGoogle Scholar
  34. Molino, M., Barnathan, E.S., Numerof, R., Clark, J., Dreyer, M., Cumashi,A., Hoxie, J.A., Schechter, N., Woolkalis, M. and Brass, L.F. (1997) Interactions of mast cell tryptase with thrombin receptors and PAR-2. J. Biol. Chem. 272, 4043–4049.CrossRefPubMedGoogle Scholar
  35. Nakae, S., Suto, H., Kakurai, M., Sedgwick, J.D., Tsai, M. and Galli, S.J. (2005) Mast cells enhance T cell activation: Importance of mast cell-derived TNF. Proc. Natl. Acad. Sci. USA 102, 6467–6472.CrossRefPubMedGoogle Scholar
  36. Ott, V.L., Cambier, J.C., Kappler, J., Marrack, P. and Swanson, B.J. (2003) Mast cell-dependent migration of effector CD8+ T cells through production of leukotriene B4. Nat. Immunol. 4, 974–981.CrossRefPubMedGoogle Scholar
  37. Pedotti, R., De Voss, J.J., Steinman, L. and Galli, S.J. (2003a) Involvement of both ‘allergic’ and ‘autoimmune’ mechanisms in EAE, MS and other autoimmune diseases. Trends Immunol. 24, 479–484.CrossRefPubMedGoogle Scholar
  38. Pedotti, R., DeVoss, J.J., Youssef, S., Mitchell, D., Wedemeyer, J., Madanat, R., Garren, H., Fontoura, P., Tsai, M., Galli, S.J., Sobel, R.A. and Steinman, L. (2003b) Multiple elements of the allergic arm of the immune response modulate autoimmune demyelination. Proc. Natl. Acad. Sci. USA 100, 1867–1872.CrossRefPubMedGoogle Scholar
  39. Redegeld, F.A. and Nijkamp, F.P. (2005) Immunoglobulin free light chains and mast cells: pivotal role in T cell-mediated immune reactions? Trends Immunol. 24, 181–185.CrossRefGoogle Scholar
  40. Rozniecki, J.J., Hauser, S., Stein, M., Lincoln, R. and Theoharides, T.C. (1995) Elevated mast cell tryptase in cerebrospinal fluid of multiple sclerosis patients. Ann. Neurol. 37, 63–66.CrossRefPubMedGoogle Scholar
  41. Ruuls, S.R., Bauer, J., Sontrop, K., Huitinga, I., ‘t Hart, B.A. and Dijkstra, C.D. (1995) Reactive oxygen species are involved in the pathogenesis of experimental allergic encephalomyelitis in Lewis rats. J. Neuroimmunol. 56, 207–217.CrossRefPubMedGoogle Scholar
  42. Salamon, P., Shoham, N.G., Gavrieli, R., Wolach, B. and Mekori, Y.A. (2005) Human mast cells release interleukin-8 and induce neutrophil chemotaxis on contact with activated T cells. Allergy 60, 1316–1319.CrossRefPubMedGoogle Scholar
  43. Smith, K.J. and McDonald, W.I. (1999) The pathophysiology of multiple sclerosis: the mechanisms underlying the production of symptoms and the natural history of the disease. Philos. Trans. R Soc. Lond. B Biol. Sci. 1390, 1649–1673.Google Scholar
  44. Stone, L.A., Smith, M.E., Albert, P.S., Bash, C.N., Maloni, H., Frank, J.A. and McFarland, H.F. (1995) Blood-brain barrier disruption on contrast-enhanced MRI in patients with mild relapsing-remitting multiple sclerosis: relationship to course, gender, and age. Neurology 45, 1122–1126.PubMedGoogle Scholar
  45. Tartaglia, L.A., Goeddel, D.V., Reynolds, C., Figari, I.S., Weber, R.F., Fendly, B.M. and Palladino, M.A., Jr. (1993) Stimulation of human T cell proliferation by specific activation of the 75-kDa tumor necrosis factor receptor. J. Immunol. 151, 4637–4641.PubMedGoogle Scholar
  46. Theoharides, T.C. and Cochrane, D.E. (2004) Critical role of mast cells in inflammatory diseases and the effect of acute stress. J. Neuroimmunol. 146, 1–12.CrossRefPubMedGoogle Scholar
  47. Theoharides, T.C., Dimitriadou, V., Letourneau, R.J., Rozniecki, J.J., Vliagoftis, H. and Boucher, W.S. (1993) Synergistic action of estradiol and myelin basic protein on mast cell secretion and brain demyelination: changes resembling early stages of demyelination. Neuroscience 57, 861–871.CrossRefPubMedGoogle Scholar
  48. Verbeek, R., Plomp, A.C., van Tol, E.A. and van Noort, J.M. (2004) The flavones luteolin and apigenin inhibit in vitro antigen-specific proliferation and interferon-gamma production by murine and human autoimmune T cells. Biochem. Pharmacol. 68, 621–629.CrossRefPubMedGoogle Scholar
  49. Zappulla, J.P., Arock, M., Mars, L.T. and Liblau, R.S. (2002) Mast cells: new targets for multiple sclerosis therapy? J. Neuroimmunol. 131, 5–20.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Theoharis C. Theoharides
    • 1
  • Duraisamy Kempuraj
    • 1
  • Betina P. Iliopoulou
    • 1
  1. 1.Departments of Pharmacology and Experimental Therapeutics; Internal Medicine and Biochemistry; Immunology ProgramTufts University School of Medicine and Tufts-New England Medical CenterBostonUSA

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