NeuroMolecular Medicine

, Volume 12, Issue 2, pp 99–132 | Cite as

Role of Cytokines as Mediators and Regulators of Microglial Activity in Inflammatory Demyelination of the CNS

  • Tobias D. Merson
  • Michele D. Binder
  • Trevor J. Kilpatrick
Review Paper

Abstract

As the resident innate immune cells of the central nervous system (CNS), microglia fulfil a critical role in maintaining tissue homeostasis and in directing and eliciting molecular responses to CNS damage. The human disease Multiple Sclerosis and animal models of inflammatory demyelination are characterized by a complex interplay between degenerative and regenerative processes, many of which are regulated and mediated by microglia. Cellular communication between microglia and other neural and immune cells is controlled to a large extent by the activity of cytokines. Here we review the role of cytokines as mediators and regulators of microglial activity in inflammatory demyelination, highlighting their importance in potentiating cell damage, promoting neuroprotection and enhancing cellular repair in a context-dependent manner.

Keywords

Microglia Macrophages Innate immunity Cytokines Interleukins Interferons Inflammatory demyelination Multiple Sclerosis Experimental autoimmune encephalomyelitis (EAE) Remyelination Oligodendrocyte Myelin 

References

  1. Abbas, A. K., Murphy, K. M., & Sher, A. (1996). Functional diversity of helper T lymphocytes. Nature, 383, 787–793.PubMedCrossRefGoogle Scholar
  2. Adams, R. A., Bauer, J., Flick, M. J., Sikorski, S. L., Nuriel, T., Lassmann, H., et al. (2007). The fibrin-derived gamma377–395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease. Journal of Experimental Medicine, 204, 571–582.PubMedCrossRefGoogle Scholar
  3. Adams, D. H., Hathaway, M., Shaw, J., Burnett, D., Elias, E., & Strain, A. J. (1991). Transforming growth factor-beta induces human T lymphocyte migration in vitro. Journal of Immunology, 147, 609–612.Google Scholar
  4. Aggarwal, S., Ghilardi, N., Xie, M. H., de Sauvage, F. J., & Gurney, A. L. (2003). Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. Journal of Biological Chemistry, 278, 1910–1914.PubMedCrossRefGoogle Scholar
  5. Akassoglou, K., Bauer, J., Kassiotis, G., Pasparakis, M., Lassmann, H., Kollias, G., et al. (1998). Oligodendrocyte apoptosis and primary demyelination induced by local TNF/p55TNF receptor signaling in the central nervous system of transgenic mice: Models for multiple sclerosis with primary oligodendrogliopathy. American Journal of Pathology, 153, 801–813.PubMedGoogle Scholar
  6. Akira, S. (2003). Toll-like receptor signaling. Journal of Biological Chemistry, 278, 38105–38108.PubMedCrossRefGoogle Scholar
  7. Aktas, O., Prozorovski, T., & Zipp, F. (2006). Death ligands and autoimmune demyelination. Neuroscientist, 12, 305–316.PubMedCrossRefGoogle Scholar
  8. Albrecht, P. J., Dahl, J. P., Stoltzfus, O. K., Levenson, R., & Levison, S. W. (2002). Ciliary neurotrophic factor activates spinal cord astrocytes, stimulating their production and release of fibroblast growth factor-2, to increase motor neuron survival. Experimental Neurology, 173, 46–62.PubMedCrossRefGoogle Scholar
  9. Allan, S. M., Tyrrell, P. J., & Rothwell, N. J. (2005). Interleukin-1 and neuronal injury. Nature Reviews Immunology, 5, 629–640.PubMedCrossRefGoogle Scholar
  10. Allione, A., Bernabei, P., Bosticardo, M., Ariotti, S., Forni, G., & Novelli, F. (1999). Nitric oxide suppresses human T lymphocyte proliferation through IFN-gamma-dependent and IFN-gamma-independent induction of apoptosis. Journal of Immunology, 163, 4182–4191.Google Scholar
  11. Aloisi, F. (2001). Immune function of microglia. Glia, 36, 165–179.PubMedCrossRefGoogle Scholar
  12. Aloisi, F., Penna, G., Cerase, J., Menendez Iglesias, B., & Adorini, L. (1997). IL-12 production by central nervous system microglia is inhibited by astrocytes. Journal of Immunology, 159, 1604–1612.Google Scholar
  13. Aloisi, F., Ria, F., & Adorini, L. (2000). Regulation of T-cell responses by CNS antigen-presenting cells: Different roles for microglia and astrocytes. Immunology Today, 21, 141–147.PubMedCrossRefGoogle Scholar
  14. Andrews, T., Zhang, P., & Bhat, N. R. (1998). TNFalpha potentiates IFNgamma-induced cell death in oligodendrocyte progenitors. Journal of Neuroscience Research, 54, 574–583.PubMedCrossRefGoogle Scholar
  15. Araujo, D. M., & Cotman, C. W. (1992). Basic FGF in astroglial, microglial, and neuronal cultures: Characterization of binding sites and modulation of release by lymphokines and trophic factors. Journal of Neuroscience, 12, 1668–1678.PubMedGoogle Scholar
  16. Arimoto, T., Choi, D. Y., Lu, X., Liu, M., Nguyen, X. V., Zheng, N., et al. (2006). Interleukin-10 protects against inflammation-mediated degeneration of dopaminergic neurons in substantia nigra. Neurobiology of Aging, 28, 894–906.CrossRefGoogle Scholar
  17. Arnett, H. A., Hellendall, R. P., Matsushima, G. K., Suzuki, K., Laubach, V. E., Sherman, P., et al. (2002). The protective role of nitric oxide in a neurotoxicant-induced demyelinating model. Journal of Immunology, 168, 427–433.Google Scholar
  18. Arnett, H. A., Mason, J., Marino, M., Suzuki, K., Matsushima, G. K., & Ting, J. P. (2001). TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nature Neuroscience, 4, 1116–1122.PubMedCrossRefGoogle Scholar
  19. Arnett, H. A., Wang, Y., Matsushima, G. K., Suzuki, K., & Ting, J. P. (2003). Functional genomic analysis of remyelination reveals importance of inflammation in oligodendrocyte regeneration. Journal of Neuroscience, 23, 9824–9832.PubMedGoogle Scholar
  20. Austin, J. W., & Fehlings, M. G. (2008). Molecular mechanisms of Fas-mediated cell death in oligodendrocytes. Journal of Neurotrauma, 25, 411–426.PubMedCrossRefGoogle Scholar
  21. Back, S., Tuohy, T., Chen, H., Wallingford, N., Craig, A., Struve, J., et al. (2005). Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation. Nature Medicine, 11, 966–972.PubMedGoogle Scholar
  22. Baerwald, K. D., & Popko, B. (1998). Developing and mature oligodendrocytes respond differently to the immune cytokine interferon-gamma. Journal of Neuroscience Research, 52, 230–239.PubMedCrossRefGoogle Scholar
  23. Bai, X. F., Shi, F. D., Xiao, B. G., Li, H. L., van der Meide, P. H., & Link, H. (1997). Nasal administration of myelin basic protein prevents relapsing experimental autoimmune encephalomyelitis in DA rats by activating regulatory cells expressing IL-4 and TGF-beta mRNA. Journal of Neuroimmunology, 80, 65–75.PubMedCrossRefGoogle Scholar
  24. Bandtlow, C. E., Meyer, M., Lindholm, D., Spranger, M., Heumann, R., & Thoenen, H. (1990). Regional and cellular codistribution of interleukin 1 beta and nerve growth factor mRNA in the adult rat brain: Possible relationship to the regulation of nerve growth factor synthesis. Journal of Cell Biology, 111, 1701–1711.PubMedCrossRefGoogle Scholar
  25. Barbara, J. A., Smith, W. B., Gamble, J. R., Van Ostade, X., Vandenabeele, P., Tavernier, J., et al. (1994). Dissociation of TNF-alpha cytotoxic and proinflammatory activities by p55 receptor- and p75 receptor-selective TNF-alpha mutants. EMBO Journal, 13, 843–850.PubMedGoogle Scholar
  26. Barnett, M. H., Henderson, A. P., & Prineas, J. W. (2006). The macrophage in MS: Just a scavenger after all? Pathology and pathogenesis of the acute MS lesion. Multiple Sclerosis, 12, 121–132.PubMedCrossRefGoogle Scholar
  27. Barnett, M. H., & Prineas, J. W. (2004). Relapsing and remitting multiple sclerosis: Pathology of the newly forming lesion. Annals of Neurology, 55, 458–468.PubMedCrossRefGoogle Scholar
  28. Barres, B. A., Schmid, R., Sendnter, M., & Raff, M. C. (1993). Multiple extracellular signals are required for long-term oligodendrocyte survival. Development, 118, 283–295.PubMedGoogle Scholar
  29. Basu, A., Krady, J. K., O’Malley, M., Styren, S. D., DeKosky, S. T., & Levison, S. W. (2002). The type 1 interleukin-1 receptor is essential for the efficient activation of microglia and the induction of multiple proinflammatory mediators in response to brain injury. Journal of Neuroscience, 22, 6071–6082.PubMedGoogle Scholar
  30. Batten, M., Li, J., Yi, S., Kljavin, N. M., Danilenko, D. M., Lucas, S., et al. (2006). Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nature Immunology, 7, 929–936.PubMedCrossRefGoogle Scholar
  31. Bauer, J., Berkenbosch, F., Van Dam, A. M., & Dijkstra, C. D. (1993). Demonstration of interleukin-1 beta in Lewis rat brain during experimental allergic encephalomyelitis by immunocytochemistry at the light and ultrastructural level. Journal of Neuroimmunology, 48, 13–21.PubMedCrossRefGoogle Scholar
  32. Baxter, A. G. (2007). The origin and application of experimental autoimmune encephalomyelitis. Nature Reviews Immunology, 7, 904–912.PubMedCrossRefGoogle Scholar
  33. Becher, B., Dodelet, V., Fedorowicz, V., & Antel, J. P. (1996). Soluble tumor necrosis factor receptor inhibits interleukin 12 production by stimulated human adult microglial cells in vitro. Journal of Clinical Investigation, 98, 1539–1543.PubMedCrossRefGoogle Scholar
  34. Becher, B., Durell, B. G., & Noelle, R. J. (2003). IL-23 produced by CNS-resident cells controls T cell encephalitogenicity during the effector phase of experimental autoimmune encephalomyelitis. Journal of Clinical Investigation, 112, 1186–1191.PubMedGoogle Scholar
  35. Becher, B., Prat, A., & Antel, J. P. (2000). Brain-immune connection: Immuno-regulatory properties of CNS-resident cells. Glia, 29, 293–304.PubMedCrossRefGoogle Scholar
  36. Beck, J., Rondot, P., Catinot, L., Falcoff, E., Kirchner, H., & Wietzerbin, J. (1988). Increased production of interferon gamma and tumor necrosis factor precedes clinical manifestation in multiple sclerosis: Do cytokines trigger off exacerbations? Acta Neurologica Scandinavica, 78, 318–323.PubMedCrossRefGoogle Scholar
  37. Begolka, W. S., Vanderlugt, C. L., Rahbe, S. M., & Miller, S. D. (1998). Differential expression of inflammatory cytokines parallels progression of central nervous system pathology in two clinically distinct models of multiple sclerosis. Journal of Immunology, 161, 4437–4446.Google Scholar
  38. Benveniste, E. N. (1998). Cytokine actions in the central nervous system. Cytokine and Growth Factor Reviews, 9, 259–275.PubMedCrossRefGoogle Scholar
  39. Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T. B., Oukka, M., et al. (2006). Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature, 441, 235–238.PubMedCrossRefGoogle Scholar
  40. Bettelli, E., Das, M. P., Howard, E. D., Weiner, H. L., Sobel, R. A., & Kuchroo, V. K. (1998). IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10- and IL-4-deficient and transgenic mice. Journal of Immunology, 161, 3299–3306.Google Scholar
  41. Bezbradica, J. S., & Medzhitov, R. (2009). Integration of cytokine and heterologous receptor signaling pathways. Nature Immunology, 10, 333–339.PubMedCrossRefGoogle Scholar
  42. Binder, M., Cate, H., Prieto, A., Kemper, D., Butzkueven, H., Gresle, M., et al. (2008). Gas6 Deficiency Increases Oligodendrocyte Loss and Microglial Activation in Response to Cuprizone-Induced Demyelination. Journal of Neuroscience, 28, 5195–5206.PubMedCrossRefGoogle Scholar
  43. Bjartmar, C., Kidd, G., Mork, S., Rudick, R., & Trapp, B. D. (2000). Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Annals of Neurology, 48, 893–901.PubMedCrossRefGoogle Scholar
  44. Blakemore, W. F. (1973). Demyelination of the superior cerebellar peduncle in the mouse induced by cuprizone. Journal of the Neurological Sciences, 20, 63–72.PubMedCrossRefGoogle Scholar
  45. Blakemore, W. F. (1982). Ethidium bromide induced demyelination in the spinal cord of the cat. Neuropathology and Applied Neurobiology, 8, 365–375.PubMedCrossRefGoogle Scholar
  46. Blakemore, W. F., & Patterson, R. C. (1978). Suppression of remyelination in the CNS by X-irradiation. Acta Neuropathologica, 42, 105–113.PubMedCrossRefGoogle Scholar
  47. Bo, L., Mork, S., Kong, P. A., Nyland, H., Pardo, C. A., & Trapp, B. D. (1994). Detection of MHC class II-antigens on macrophages and microglia, but not on astrocytes and endothelia in active multiple sclerosis lesions. Journal of Neuroimmunology, 51, 135–146.PubMedCrossRefGoogle Scholar
  48. Brahmachari, S., & Pahan, K. (2009). Suppression of regulatory T cells by IL-12p40 homodimer via nitric oxide. Journal of Immunology, 183, 2045–2058.CrossRefGoogle Scholar
  49. Brogi, A., Strazza, M., Melli, M., & Costantino-Ceccarini, E. (1997). Induction of intracellular ceramide by interleukin-1 beta in oligodendrocytes. Journal of Cellular Biochemistry, 66, 532–541.PubMedCrossRefGoogle Scholar
  50. Brok, H. P., van Meurs, M., Blezer, E., Schantz, A., Peritt, D., Treacy, G., et al. (2002). Prevention of experimental autoimmune encephalomyelitis in common marmosets using an anti-IL-12p40 monoclonal antibody. Journal of Immunology, 169, 6554–6563.Google Scholar
  51. Bruck, W., Porada, P., Poser, S., Rieckmann, P., Hanefeld, F., Kretzschmar, H. A., et al. (1995). Monocyte/macrophage differentiation in early multiple sclerosis lesions. Annals of Neurology, 38, 788–796.PubMedCrossRefGoogle Scholar
  52. Butovsky, O., Ziv, Y., Schwartz, A., Landa, G., Talpalar, A. E., Pluchino, S., et al. (2006). Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Molecular and Cellular Neurosciences, 31, 149–160.PubMedCrossRefGoogle Scholar
  53. Butti, E., Bergami, A., Recchia, A., Brambilla, E., Del Carro, U., Amadio, S., et al. (2008). IL4 gene delivery to the CNS recruits regulatory T cells and induces clinical recovery in mouse models of multiple sclerosis. Gene Therapy, 15, 504–515.PubMedCrossRefGoogle Scholar
  54. Butzkueven, H., Emery, B., Cipriani, T., Marriott, M. P., & Kilpatrick, T. J. (2006). Endogenous leukemia inhibitory factor production limits autoimmune demyelination and oligodendrocyte loss. Glia, 53, 696–703.PubMedCrossRefGoogle Scholar
  55. Butzkueven, H., Zhang, J. G., Soilu-Hanninen, M., Hochrein, H., Chionh, F., Shipham, K. A., et al. (2002). LIF receptor signaling limits immune-mediated demyelination by enhancing oligodendrocyte survival. Nature Medicine, 8, 613–619.PubMedCrossRefGoogle Scholar
  56. Calabresi, P. A., Fields, N. S., Maloni, H. W., Hanham, A., Carlino, J., Moore, J., et al. (1998). Phase 1 trial of transforming growth factor beta 2 in chronic progressive MS. Neurology, 51, 289–292.PubMedGoogle Scholar
  57. Carpentier, P. A., Duncan, D. S., & Miller, S. D. (2008). Glial toll-like receptor signaling in central nervous system infection and autoimmunity. Brain, Behavior, and Immunity, 22, 140–147.PubMedCrossRefGoogle Scholar
  58. Carrier, Y., Yuan, J., Kuchroo, V. K., & Weiner, H. L. (2007). Th3 cells in peripheral tolerance. I. Induction of Foxp3-positive regulatory T cells by Th3 cells derived from TGF-beta T cell-transgenic mice. Journal of Immunology, 178, 179–185.Google Scholar
  59. Casaccia-Bonnefil, P., Aibel, L., & Chao, M. V. (1996). Central glial and neuronal populations display differential sensitivity to ceramide-dependent cell death. Journal of Neuroscience Research, 43, 382–389.PubMedCrossRefGoogle Scholar
  60. Chabot, S., & Yong, V. W. (2000). Interferon beta-1b increases interleukin-10 in a model of T cell-microglia interaction: Relevance to MS. Neurology, 55, 1497–1505.PubMedGoogle Scholar
  61. Chakraborty, G., Ziemba, S., Drivas, A., & Ledeen, R. W. (1997). Myelin contains neutral sphingomyelinase activity that is stimulated by tumor necrosis factor-alpha. Journal of Neuroscience Research, 50, 466–476.PubMedCrossRefGoogle Scholar
  62. Chan, A., Magnus, T., & Gold, R. (2001). Phagocytosis of apoptotic inflammatory cells by microglia and modulation by different cytokines: Mechanism for removal of apoptotic cells in the inflamed nervous system. Glia, 33, 87–95.PubMedCrossRefGoogle Scholar
  63. Chan, A., Seguin, R., Magnus, T., Papadimitriou, C., Toyka, K. V., Antel, J. P., et al. (2003). Phagocytosis of apoptotic inflammatory cells by microglia and its therapeutic implications: Termination of CNS autoimmune inflammation and modulation by interferon-beta. Glia, 43, 231–242.PubMedCrossRefGoogle Scholar
  64. Chao, C. C., Molitor, T. W., & Hu, S. (1993). Neuroprotective role of IL-4 against activated microglia. Journal of Immunology, 151, 1473–1481.Google Scholar
  65. Chari, D., Zhao, C., Kotter, M. R., Blakemore, W., & Franklin, R. J. (2006). Corticosteroids delay remyelination of experimental demyelination in the rodent central nervous system. Journal of Neuroscience Research, 83, 594–605.PubMedCrossRefGoogle Scholar
  66. Chen, G., & Goeddel, D. V. (2002). TNF-R1 signaling: A beautiful pathway. Science, 296, 1634–1635.PubMedCrossRefGoogle Scholar
  67. Chen, L. Z., Hochwald, G. M., Huang, C., Dakin, G., Tao, H., Cheng, C., et al. (1998). Gene therapy in allergic encephalomyelitis using myelin basic protein-specific T cells engineered to express latent transforming growth factor-beta1. Proceedings of the National Academy of Sciences of the United States of America, 95, 12516–12521.PubMedCrossRefGoogle Scholar
  68. Chen, Y., Kuchroo, V. K., Inobe, J., Hafler, D. A., & Weiner, H. L. (1994). Regulatory T cell clones induced by oral tolerance: Suppression of autoimmune encephalomyelitis. Science, 265, 1237–1240.PubMedCrossRefGoogle Scholar
  69. Chitnis, T., Najafian, N., Benou, C., Salama, A. D., Grusby, M. J., Sayegh, M. H., et al. (2001). Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis. Journal of Clinical Investigation, 108, 739–747.PubMedGoogle Scholar
  70. Clerico, M., Contessa, G., & Durelli, L. (2007). Interferon-beta1a for the treatment of multiple sclerosis. Expert Opinion on Biological Therapy, 7, 535–542.PubMedCrossRefGoogle Scholar
  71. Constantinescu, C. S., Goodman, D. B., Hilliard, B., Wysocka, M., & Cohen, J. A. (2000). Murine macrophages stimulated with central and peripheral nervous system myelin or purified myelin proteins release inflammatory products. Neuroscience Letters, 287, 171–174.PubMedCrossRefGoogle Scholar
  72. Constantinescu, C. S., Wysocka, M., Hilliard, B., Ventura, E. S., Lavi, E., Trinchieri, G., et al. (1998). Antibodies against IL-12 prevent superantigen-induced and spontaneous relapses of experimental autoimmune encephalomyelitis. Journal of Immunology, 161, 5097–5104.Google Scholar
  73. Crisi, G. M., Santambrogio, L., Hochwald, G. M., Smith, S. R., Carlino, J. A., & Thorbecke, G. J. (1995). Staphylococcal enterotoxin B and tumor-necrosis factor-alpha-induced relapses of experimental allergic encephalomyelitis: Protection by transforming growth factor-beta and interleukin-10. European Journal of Immunology, 25, 3035–3040.PubMedCrossRefGoogle Scholar
  74. Cua, D. J., Hinton, D. R., & Stohlman, S. A. (1995). Self-antigen-induced Th2 responses in experimental allergic encephalomyelitis (EAE)-resistant mice. Th2-mediated suppression of autoimmune disease. Journal of Immunology, 155, 4052–4059.Google Scholar
  75. Cua, D., Sherlock, J., Chen, Y., Murphy, C., Joyce, B., Seymour, B., et al. (2003). Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature, 421, 744–748.PubMedCrossRefGoogle Scholar
  76. D’Souza, S. D., Bonetti, B., Balasingam, V., Cashman, N. R., Barker, P. A., Troutt, A. B., et al. (1996). Multiple sclerosis: Fas signaling in oligodendrocyte cell death. Journal of Experimental Medicine, 184, 2361–2370.PubMedCrossRefGoogle Scholar
  77. da Cunha, A., & Vitkovic, L. (1992). Transforming growth factor-beta 1 (TGF-beta 1) expression and regulation in rat cortical astrocytes. Journal of Neuroimmunology, 36, 157–169.PubMedCrossRefGoogle Scholar
  78. Dal Canto, M. C., & Lipton, H. L. (1975). Primary demyelination in Theiler’s virus infection. An ultrastructural study. Laboratory Investigation, 33, 626–637.PubMedGoogle Scholar
  79. De Groot, C. J., Montagne, L., Barten, A. D., Sminia, P., & Van Der Valk, P. (1999). Expression of transforming growth factor (TGF)-beta1, -beta2, and -beta3 isoforms and TGF-beta type I and type II receptors in multiple sclerosis lesions and human adult astrocyte cultures. Journal of Neuropathology and Experimental Neurology, 58, 174–187.PubMedCrossRefGoogle Scholar
  80. de Herve, M. G., Delfraissy, J. F., & Taoufik, Y. (2001). Following direct CD40 activation, human primary microglial cells produce IL-12 p40 but not bioactive IL-12 p70. Cytokine, 14, 88–96.CrossRefGoogle Scholar
  81. De Simone, R., Ambrosini, E., Carnevale, D., Ajmone-Cat, M. A., & Minghetti, L. (2007). NGF promotes microglial migration through the activation of its high affinity receptor: Modulation by TGF-beta. Journal of Neuroimmunology, 190, 53–60.PubMedCrossRefGoogle Scholar
  82. Deckert-Schluter, M., Bluethmann, H., Kaefer, N., Rang, A., & Schluter, D. (1999). Interferon-gamma receptor-mediated but not tumor necrosis factor receptor type 1- or type 2-mediated signaling is crucial for the activation of cerebral blood vessel endothelial cells and microglia in murine Toxoplasma encephalitis. American Journal of Pathology, 154, 1549–1561.PubMedGoogle Scholar
  83. Dendorfer, U., Oettgen, P., & Libermann, T. A. (1994). Multiple regulatory elements in the interleukin-6 gene mediate induction by prostaglandins, cyclic AMP, and lipopolysaccharide. Molecular and Cellular Biology, 14, 4443–4454.PubMedGoogle Scholar
  84. Dheen, S. T., Kaur, C., & Ling, E. A. (2007). Microglial activation and its implications in the brain diseases. Current Medicinal Chemistry, 14, 1189–1197.PubMedCrossRefGoogle Scholar
  85. Dinarello, C. A., Cannon, J. G., Wolff, S. M., Bernheim, H. A., Beutler, B., Cerami, A., et al. (1986). Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. Journal of Experimental Medicine, 163, 1433–1450.PubMedCrossRefGoogle Scholar
  86. Dower, S. K., Kronheim, S. R., Hopp, T. P., Cantrell, M., Deeley, M., Gillis, S., et al. (1986). The cell surface receptors for interleukin-1 alpha and interleukin-1 beta are identical. Nature, 324, 266–268.PubMedCrossRefGoogle Scholar
  87. Dower, S. K., Kronheim, S. R., March, C. J., Conlon, P. J., Hopp, T. P., Gillis, S., et al. (1985). Detection and characterization of high affinity plasma membrane receptors for human interleukin 1. Journal of Experimental Medicine, 162, 501–515.PubMedCrossRefGoogle Scholar
  88. Dowling, P., Shang, G., Raval, S., Menonna, J., Cook, S., & Husar, W. (1996). Involvement of the CD95 (APO-1/Fas) receptor/ligand system in multiple sclerosis brain. Journal of Experimental Medicine, 184, 1513–1518.PubMedCrossRefGoogle Scholar
  89. Drescher, K. M., Murray, P. D., Lin, X., Carlino, J. A., & Rodriguez, M. (2000). TGF-beta 2 reduces demyelination, virus antigen expression, and macrophage recruitment in a viral model of multiple sclerosis. Journal of Immunology, 164, 3207–3213.Google Scholar
  90. Dunne, A. and O’Neill L. A. (2003) The interleukin-1 receptor/Toll-like receptor superfamily: Signal transduction during inflammation and host defense. Sci STKE 2003, re3.Google Scholar
  91. Duong, T. T., Finkelman, F. D., Singh, B., & Strejan, G. H. (1994). Effect of anti-interferon-gamma monoclonal antibody treatment on the development of experimental allergic encephalomyelitis in resistant mouse strains. Journal of Neuroimmunology, 53, 101–107.PubMedCrossRefGoogle Scholar
  92. Duong, T. T., St Louis, J., Gilbert, J. J., Finkelman, F. D., & Strejan, G. H. (1992). Effect of anti-interferon-gamma and anti-interleukin-2 monoclonal antibody treatment on the development of actively and passively induced experimental allergic encephalomyelitis in the SJL/J mouse. Journal of Neuroimmunology, 36, 105–115.PubMedCrossRefGoogle Scholar
  93. Emery, B., Cate, H. S., Marriott, M., Merson, T., Binder, M. D., Snell, C., et al. (2006). Suppressor of cytokine signaling 3 limits protection of leukemia inhibitory factor receptor signaling against central demyelination. Proceedings of the National Academy of Sciences of the United States of America, 103, 7859–7864.PubMedCrossRefGoogle Scholar
  94. Erb, K. J., Ruger, B., von Brevern, M., Ryffel, B., Schimpl, A., & Rivett, K. (1997). Constitutive expression of interleukin (IL)-4 in vivo causes autoimmune-type disorders in mice. Journal of Experimental Medicine, 185, 329–339.PubMedCrossRefGoogle Scholar
  95. Fabry, Z., Topham, D. J., Fee, D., Herlein, J., Carlino, J. A., Hart, M. N., et al. (1995). TGF-beta 2 decreases migration of lymphocytes in vitro and homing of cells into the central nervous system in vivo. Journal of Immunology, 155, 325–332.Google Scholar
  96. Falcone, M., Rajan, A. J., Bloom, B. R., & Brosnan, C. F. (1998). A critical role for IL-4 in regulating disease severity in experimental allergic encephalomyelitis as demonstrated in IL-4-deficient C57BL/6 mice and BALB/c mice. Journal of Immunology, 160, 4822–4830.Google Scholar
  97. Fantini, M. C., Becker, C., Monteleone, G., Pallone, F., Galle, P. R., & Neurath, M. F. (2004). Cutting edge: TGF-beta induces a regulatory phenotype in CD4 + CD25- T cells through Foxp3 induction and down-regulation of Smad7. Journal of Immunology, 172, 5149–5153.Google Scholar
  98. Faria, A. M., & Weiner, H. L. (2005). Oral tolerance. Immunological Reviews, 206, 232–259.PubMedCrossRefGoogle Scholar
  99. Farina, C., Aloisi, F., & Meinl, E. (2007). Astrocytes are active players in cerebral innate immunity. Trends in Immunology, 28, 138–145.PubMedCrossRefGoogle Scholar
  100. Fassbender, K., Ragoschke, A., Rossol, S., Schwartz, A., Mielke, O., Paulig, A., et al. (1998). Increased release of interleukin-12p40 in MS: Association with intracerebral inflammation. Neurology, 51, 753–758.PubMedGoogle Scholar
  101. Fazakerley, J. K., & Walker, R. (2003). Virus demyelination. Journal of Neurovirology, 9, 148–164.PubMedGoogle Scholar
  102. Ferber, I. A., Brocke, S., Taylor-Edwards, C., Ridgway, W., Dinisco, C., Steinman, L., et al. (1996). Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). Journal of Immunology, 156, 5–7.Google Scholar
  103. Ferguson, B., Matyszak, M. K., Esiri, M. M., & Perry, V. H. (1997). Axonal damage in acute multiple sclerosis lesions. Brain, 120(Pt 3), 393–399.PubMedCrossRefGoogle Scholar
  104. Ferrari, C. C., Depino, A. M., Prada, F., Muraro, N., Campbell, S., Podhajcer, O., et al. (2004). Reversible demyelination, blood-brain barrier breakdown, and pronounced neutrophil recruitment induced by chronic IL-1 expression in the brain. American Journal of Pathology, 165, 1827–1837.PubMedGoogle Scholar
  105. Fischer, H. G., Bielinsky, A. K., Nitzgen, B., Daubener, W., & Hadding, U. (1993). Functional dichotomy of mouse microglia developed in vitro: Differential effects of macrophage and granulocyte/macrophage colony-stimulating factor on cytokine secretion and antitoxoplasmic activity. Journal of Neuroimmunology, 45, 193–201.PubMedCrossRefGoogle Scholar
  106. Flowers, L. O., Johnson, H. M., Mujtaba, M. G., Ellis, M. R., Haider, S. M., & Subramaniam, P. S. (2004). Characterization of a peptide inhibitor of Janus kinase 2 that mimics suppressor of cytokine signaling 1 function. Journal of Immunology, 172, 7510–7518.Google Scholar
  107. Fontenot, J. D., Gavin, M. A., & Rudensky, A. Y. (2003). Foxp3 programs the development and function of CD4 + CD25 + regulatory T cells. Nature Immunology, 4, 330–336.PubMedCrossRefGoogle Scholar
  108. Foote, A. K., & Blakemore, W. F. (2005). Inflammation stimulates remyelination in areas of chronic demyelination. Brain, 128, 528–539.PubMedCrossRefGoogle Scholar
  109. Franklin, R. J., & ffrench-Constant, C. (2008). Remyelination in the CNS: From biology to therapy. Nature Reviews Neuroscience, 9, 839–855.PubMedCrossRefGoogle Scholar
  110. Frei, K., Eugster, H. P., Bopst, M., Constantinescu, C. S., Lavi, E., & Fontana, A. (1997). Tumor necrosis factor alpha and lymphotoxin alpha are not required for induction of acute experimental autoimmune encephalomyelitis. Journal of Experimental Medicine, 185, 2177–2182.PubMedCrossRefGoogle Scholar
  111. Frei, K., Fredrikson, S., Fontana, A., & Link, H. (1991). Interleukin-6 is elevated in plasma in multiple sclerosis. Journal of Neuroimmunology, 31, 147–153.PubMedCrossRefGoogle Scholar
  112. Friedman, W. J., Thakur, S., Seidman, L., & Rabson, A. B. (1996). Regulation of nerve growth factor mRNA by interleukin-1 in rat hippocampal astrocytes is mediated by NFkappaB. Journal of Biological Chemistry, 271, 31115–31120.PubMedCrossRefGoogle Scholar
  113. Furlan, R., Poliani, P. L., Galbiati, F., Bergami, A., Grimaldi, L. M., Comi, G., et al. (1998). Central nervous system delivery of interleukin 4 by a nonreplicative herpes simplex type 1 viral vector ameliorates autoimmune demyelination. Human Gene Therapy, 9, 2605–2617.PubMedCrossRefGoogle Scholar
  114. Gallo, V., & Armstrong, R. C. (2008). Myelin repair strategies: A cellular view. Current Opinion in Neurology, 21, 278–283.PubMedCrossRefGoogle Scholar
  115. Gao, X., Gillig, T. A., Ye, P., D’Ercole, A. J., Matsushima, G. K., & Popko, B. (2000). Interferon-gamma protects against cuprizone-induced demyelination. Molecular and Cellular Neurosciences, 16, 338–349.PubMedCrossRefGoogle Scholar
  116. Gaupp, S., Cannella, B., & Raine, C. S. (2008). Amelioration of experimental autoimmune encephalomyelitis in IL-4Ralpha-/- mice implicates compensatory up-regulation of Th2-type cytokines. American Journal of Pathology, 173, 119–129.PubMedCrossRefGoogle Scholar
  117. Germann, T., Gately, M. K., Schoenhaut, D. S., Lohoff, M., Mattner, F., Fischer, S., et al. (1993). Interleukin-12/T cell stimulating factor, a cytokine with multiple effects on T helper type 1 (Th1) but not on Th2 cells. European Journal of Immunology, 23, 1762–1770.PubMedCrossRefGoogle Scholar
  118. Gijbels, K., Brocke, S., Abrams, J. S., & Steinman, L. (1995). Administration of neutralizing antibodies to interleukin-6 (IL-6) reduces experimental autoimmune encephalomyelitis and is associated with elevated levels of IL-6 bioactivity in central nervous system and circulation. Molecular Medicine, 1, 795–805.PubMedGoogle Scholar
  119. Gil-Guerrero, L., Dotor, J., Huibregtse, I. L., Casares, N., Lopez-Vazquez, A. B., Rudilla, F., et al. (2008). In vitro and in vivo down-regulation of regulatory T cell activity with a peptide inhibitor of TGF-beta1. Journal of Immunology, 181, 126–135.Google Scholar
  120. Giulian, D., Johnson, B., Krebs, J. F., George, J. K., & Tapscott, M. (1991). Microglial mitogens are produced in the developing and injured mammalian brain. Journal of Cell Biology, 112, 323–333.PubMedCrossRefGoogle Scholar
  121. Giulian, D., & Lachman, L. B. (1985). Interleukin-1 stimulation of astroglial proliferation after brain injury. Science, 228, 497–499.PubMedCrossRefGoogle Scholar
  122. Gold, R. (2006). Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain, 129, 1953–1971.PubMedCrossRefGoogle Scholar
  123. Gough, D. J., Levy, D. E., Johnstone, R. W., & Clarke, C. J. (2008). IFNgamma signaling-does it mean JAK-STAT? Cytokine and Growth Factor Reviews, 19, 383–394.PubMedCrossRefGoogle Scholar
  124. Gran, B., Zhang, G. X., Yu, S., Li, J., Chen, X. H., Ventura, E. S., et al. (2002). IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: Evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. Journal of Immunology, 169, 7104–7110.Google Scholar
  125. Greenfeder, S. A., Nunes, P., Kwee, L., Labow, M., Chizzonite, R. A., & Ju, G. (1995). Molecular cloning and characterization of a second subunit of the interleukin 1 receptor complex. Journal of Biological Chemistry, 270, 13757–13765.PubMedCrossRefGoogle Scholar
  126. Grommes, C., Lee, C. Y., Wilkinson, B. L., Jiang, Q., Koenigsknecht-Talboo, J. L., Varnum, B., et al. (2008). Regulation of microglial phagocytosis and inflammatory gene expression by Gas6 acting on the Axl/Mer family of tyrosine kinases. Journal of Neuroimmune Pharmacology, 3, 130–140.PubMedCrossRefGoogle Scholar
  127. Guha, M., & Mackman, N. (2001). LPS induction of gene expression in human monocytes. Cellular Signalling, 13, 85–94.PubMedCrossRefGoogle Scholar
  128. Guo, B., Chang, E., & Cheng, G. (2008). The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice. Journal of Clinical Investigation, 118, 1680–1690.PubMedCrossRefGoogle Scholar
  129. Haak, S., Croxford, A. L., Kreymborg, K., Heppner, F. L., Pouly, S., Becher, B., et al. (2009). IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. Journal of Clinical Investigation, 119, 61–69.PubMedGoogle Scholar
  130. Hall, S. M. (1972). The effect of injections of lysophosphatidyl choline into white matter of the adult mouse spinal cord. Journal of Cell Science, 10, 535–546.PubMedGoogle Scholar
  131. Hallenbeck, J. M. (2002). The many faces of tumor necrosis factor in stroke. Nature Medicine, 8, 1363–1368.PubMedCrossRefGoogle Scholar
  132. Hauser, S. L., Doolittle, T. H., Lincoln, R., Brown, R. H., & Dinarello, C. A. (1990). Cytokine accumulations in CSF of multiple sclerosis patients: Frequent detection of interleukin-1 and tumor necrosis factor but not interleukin-6. Neurology, 40, 1735–1739.PubMedGoogle Scholar
  133. Healy, A. M., Schwartz, J. J., Zhu, X., Herrick, B. E., Varnum, B., & Farber, H. W. (2001). Gas 6 promotes Axl-mediated survival in pulmonary endothelial cells. American Journal of Physiology Lung Cellular and Molecular Physiology, 280, L1273–L1281.PubMedGoogle Scholar
  134. Hebenstreit, D., Wirnsberger, G., Horejs-Hoeck, J., & Duschl, A. (2006). Signaling mechanisms, interaction partners, and target genes of STAT6. Cytokine and Growth Factor Reviews, 17, 173–188.PubMedCrossRefGoogle Scholar
  135. Heine, S., Ebnet, J., Maysami, S., & Stangel, M. (2006). Effects of interferon-beta on oligodendroglial cells. Journal of Neuroimmunology, 177, 173–180.PubMedCrossRefGoogle Scholar
  136. Held, W., Meyermann, R., Qin, Y., & Mueller, C. (1993). Perforin and tumor necrosis factor alpha in the pathogenesis of experimental allergic encephalomyelitis: Comparison of autoantigen induced and transferred disease in Lewis rats. Journal of Autoimmunity, 6, 311–322.PubMedCrossRefGoogle Scholar
  137. Hemmi, S., Böhln, R., Stark, G., Di Marco, F., & Aguet, M. (1994). A novel member of the interferon receptor family complements functionality of the murine interferon γ receptor in human cells. Cell, 76, 803–810.PubMedCrossRefGoogle Scholar
  138. Hendriks, J. J., Slaets, H., Carmans, S., de Vries, H. E., Dijkstra, C. D., Stinissen, P., et al. (2008). Leukemia inhibitory factor modulates production of inflammatory mediators and myelin phagocytosis by macrophages. Journal of Neuroimmunology, 204, 52–57.PubMedCrossRefGoogle Scholar
  139. Hendriks, J. J., Teunissen, C. E., de Vries, H. E., & Dijkstra, C. D. (2005). Macrophages and neurodegeneration. Brain Research. Brain Research Reviews, 48, 185–195.PubMedCrossRefGoogle Scholar
  140. Heppner, F. L., Greter, M., Marino, D., Falsig, J., Raivich, G., Hovelmeyer, N., et al. (2005). Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nature Medicine, 11, 146–152.PubMedCrossRefGoogle Scholar
  141. Herrera-Molina, R., & von Bernhardi, R. (2005). Transforming growth factor-beta 1 produced by hippocampal cells modulates microglial reactivity in culture. Neurobiology of Diseases, 19, 229–236.CrossRefGoogle Scholar
  142. Hershkoviz, R., Mor, F., Gilat, D., Cohen, I. R., & Lider, O. (1992). T cells in the spinal cord in experimental autoimmune encephalomyelitis are matrix adherent and secrete tumor necrosis factor alpha. Journal of Neuroimmunology, 37, 161–166.PubMedCrossRefGoogle Scholar
  143. Heyen, J. R., Ye, S., Finck, B. N., & Johnson, R. W. (2000). Interleukin (IL)-10 inhibits IL-6 production in microglia by preventing activation of NF-kappaB. Brain Research. Molecular Brain Research, 77, 138–147.PubMedCrossRefGoogle Scholar
  144. Hinks, G. L., & Franklin, R. J. (1999). Distinctive patterns of PDGF-A, FGF-2, IGF-I, and TGF-beta1 gene expression during remyelination of experimentally-induced spinal cord demyelination. Molecular and Cellular Neurosciences, 14, 153–168.PubMedCrossRefGoogle Scholar
  145. Hinks, G. L., & Franklin, R. J. (2000). Delayed changes in growth factor gene expression during slow remyelination in the CNS of aged rats. Molecular and Cellular Neurosciences, 16, 542–556.PubMedCrossRefGoogle Scholar
  146. Hiscott, J., Marois, J., Garoufalis, J., D’Addario, M., Roulston, A., Kwan, I., et al. (1993). Characterization of a functional NF-kappa B site in the human interleukin 1 beta promoter: Evidence for a positive autoregulatory loop. Molecular and Cellular Biology, 13, 6231–6240.PubMedGoogle Scholar
  147. Hoehn, H. J., Kress, Y., Sohn, A., Brosnan, C. F., Bourdon, S., & Shafit-Zagardo, B. (2008). Axl-/- mice have delayed recovery and prolonged axonal damage following cuprizone toxicity. Brain Research, 1240, 1–11.PubMedCrossRefGoogle Scholar
  148. Hofman, F. M., Hinton, D. R., Johnson, K., & Merrill, J. E. (1989). Tumor necrosis factor identified in multiple sclerosis brain. Journal of Experimental Medicine, 170, 607–612.PubMedCrossRefGoogle Scholar
  149. Hofman, F. M., von Hanwehr, R. I., Dinarello, C. A., Mizel, S. B., Hinton, D., & Merrill, J. E. (1986). Immunoregulatory molecules and IL 2 receptors identified in multiple sclerosis brain. Journal of Immunology, 136, 3239–3245.Google Scholar
  150. Hori, S., Nomura, T., & Sakaguchi, S. (2003). Control of regulatory T cell development by the transcription factor Foxp3. Science, 299, 1057–1061.PubMedCrossRefGoogle Scholar
  151. Horvath, C. M. (2004) The Jak-STAT pathway stimulated by interferon gamma. Sci STKE 2004, tr8.Google Scholar
  152. Hoshino, K., Kaisho, T., Iwabe, T., Takeuchi, O., & Akira, S. (2002). Differential involvement of IFN-beta in Toll-like receptor-stimulated dendritic cell activation. International Immunology, 14, 1225–1231.PubMedCrossRefGoogle Scholar
  153. Hövelmeyer, N., Hao, Z., Kranidioti, K., Kassiotis, G., Buch, T., Frommer, F., et al. (2005). Apoptosis of oligodendrocytes via Fas and TNF-R1 is a key event in the induction of experimental autoimmune encephalomyelitis. Journal of Immunology, 175, 5875–5884.Google Scholar
  154. Hsieh, J. (2004). IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes. Journal of Cell Biology, 164, 111–122.PubMedCrossRefGoogle Scholar
  155. Huber, M., Steinwald, V., Guralnik, A., Brustle, A., Kleemann, P., Rosenplanter, C., et al. (2008). IL-27 inhibits the development of regulatory T cells via STAT3. International Immunology, 20, 223–234.PubMedCrossRefGoogle Scholar
  156. Hunter, C. A. (2005). New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nature Reviews Immunology, 5, 521–531.PubMedCrossRefGoogle Scholar
  157. Ichijo, H. (1999). From receptors to stress-activated MAP kinases. Oncogene, 18, 6087–6093.PubMedCrossRefGoogle Scholar
  158. Ichikawa, M., Koh, C. S., Inoue, A., Tsuyusaki, J., Yamazaki, M., Inaba, Y., et al. (2000). Anti-IL-12 antibody prevents the development and progression of multiple sclerosis-like relapsing–remitting demyelinating disease in NOD mice induced with myelin oligodendrocyte glycoprotein peptide. Journal of Neuroimmunology, 102, 56–66.PubMedCrossRefGoogle Scholar
  159. Ihle, J. N. (1995). Cytokine receptor signalling. Nature, 377, 591–594.PubMedCrossRefGoogle Scholar
  160. Irvine, K., & Blakemore, W. (2008). Remyelination protects axons from demyelination-associated axon degeneration. Brain, 131, 1464–1477.PubMedCrossRefGoogle Scholar
  161. Issazadeh, S., Ljungdahl, A., Hojeberg, B., Mustafa, M., & Olsson, T. (1995). Cytokine production in the central nervous system of Lewis rats with experimental autoimmune encephalomyelitis: Dynamics of mRNA expression for interleukin-10, interleukin-12, cytolysin, tumor necrosis factor alpha and tumor necrosis factor beta. Journal of Neuroimmunology, 61, 205–212.PubMedCrossRefGoogle Scholar
  162. Jana, M., Dasgupta, S., Pal, U., & Pahan, K. (2009). IL-12 p40 homodimer, the so-called biologically inactive molecule, induces nitric oxide synthase in microglia via IL-12R beta 1. Glia, 57, 1553–1565.PubMedCrossRefGoogle Scholar
  163. Jana, M., Dasgupta, S., Saha, R. N., Liu, X., & Pahan, K. (2003). Induction of tumor necrosis factor-alpha (TNF-alpha) by interleukin-12 p40 monomer and homodimer in microglia and macrophages. Journal of Neurochemistry, 86, 519–528.PubMedCrossRefGoogle Scholar
  164. Jana, M., Liu, X., Koka, S., Ghosh, S., Petro, T. M., & Pahan, K. (2001). Ligation of CD40 stimulates the induction of nitric-oxide synthase in microglial cells. Journal of Biological Chemistry, 276, 44527–44533.PubMedCrossRefGoogle Scholar
  165. Jana, M., & Pahan, K. (2009a). IL-12 p40 homodimer, but not IL-12 p70, induces the expression of IL-16 in microglia and macrophages. Molecular Immunology, 46, 773–783.PubMedCrossRefGoogle Scholar
  166. Jana, M., & Pahan, K. (2009b). Induction of lymphotoxin-alpha by interleukin-12 p40 homodimer, the so-called biologically inactive molecule, but not IL-12 p70. Immunology, 127, 312–325.PubMedCrossRefGoogle Scholar
  167. Jander, S., Pohl, J., D’Urso, D., Gillen, C., & Stoll, G. (1998). Time course and cellular localization of interleukin-10 mRNA and protein expression in autoimmune inflammation of the rat central nervous system. American Journal of Pathology, 152, 975–982.PubMedGoogle Scholar
  168. Jang, S., Kelley, K. W., & Johnson, R. W. (2008). Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. Proceedings of the National Academy of Sciences of the United States of America, 105, 7534–7539.PubMedCrossRefGoogle Scholar
  169. Jeohn, G. H., Kong, L. Y., Wilson, B., Hudson, P., & Hong, J. S. (1998). Synergistic neurotoxic effects of combined treatments with cytokines in murine primary mixed neuron/glia cultures. Journal of Neuroimmunology, 85, 1–10.PubMedCrossRefGoogle Scholar
  170. Jin, Y. H., Mohindru, M., Kang, M. H., Fuller, A. C., Kang, B., Gallo, D., et al. (2007). Differential virus replication, cytokine production, and antigen-presenting function by microglia from susceptible and resistant mice infected with Theiler’s virus. Journal of Virology, 81, 11690–11702.PubMedCrossRefGoogle Scholar
  171. John, G. R., Shankar, S. L., Shafit-Zagardo, B., Massimi, A., Lee, S. C., Raine, C. S., et al. (2002). Multiple sclerosis: Re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nature Medicine, 8, 1115–1121.PubMedCrossRefGoogle Scholar
  172. Johns, L. D., Flanders, K. C., Ranges, G. E., & Sriram, S. (1991). Successful treatment of experimental allergic encephalomyelitis with transforming growth factor-beta 1. Journal of Immunology, 147, 1792–1796.Google Scholar
  173. Johns, L. D., & Sriram, S. (1993). Experimental allergic encephalomyelitis: Neutralizing antibody to TGF beta 1 enhances the clinical severity of the disease. Journal of Neuroimmunology, 47, 1–7.PubMedCrossRefGoogle Scholar
  174. Josefowicz, S. Z., & Rudensky, A. (2009). Control of regulatory T cell lineage commitment and maintenance. Immunity, 30, 616–625.PubMedCrossRefGoogle Scholar
  175. Kamiya, S., Owaki, T., Morishima, N., Fukai, F., Mizuguchi, J., & Yoshimoto, T. (2004). An indispensable role for STAT1 in IL-27-induced T-bet expression but not proliferation of naive CD4 + T cells. Journal of Immunology, 173, 3871–3877.Google Scholar
  176. Katz-Levy, Y., Neville, K. L., Padilla, J., Rahbe, S., Begolka, W. S., Girvin, A. M., et al. (2000). Temporal development of autoreactive Th1 responses and endogenous presentation of self myelin epitopes by central nervous system-resident APCs in Theiler’s virus-infected mice. Journal of Immunology, 165, 5304–5314.Google Scholar
  177. Kawanokuchi, J., Mizuno, T., Kato, H., Mitsuma, N., & Suzumura, A. (2004). Effects of interferon-beta on microglial functions as inflammatory and antigen presenting cells in the central nervous system. Neuropharmacology, 46, 734–742.PubMedCrossRefGoogle Scholar
  178. Kawanokuchi, J., Shimizu, K., Nitta, A., Yamada, K., Mizuno, T., Takeuchi, H., et al. (2008). Production and functions of IL-17 in microglia. Journal of Neuroimmunology, 194, 54–61.PubMedCrossRefGoogle Scholar
  179. Keating, P., O’Sullivan, D., Tierney, J. B., Kenwright, D., Miromoeini, S., Mawasse, L., et al. (2009). Protection from EAE by IL-4Ralpha(-/-) macrophages depends upon T regulatory cell involvement. Immunology and Cell Biology, 87, 534–545.PubMedCrossRefGoogle Scholar
  180. Kennedy, M. K., Torrance, D. S., Picha, K. S., & Mohler, K. M. (1992). Analysis of cytokine mRNA expression in the central nervous system of mice with experimental autoimmune encephalomyelitis reveals that IL-10 mRNA expression correlates with recovery. Journal of Immunology, 149, 2496–2505.Google Scholar
  181. Kerr, B. J., & Patterson, P. H. (2005). Leukemia inhibitory factor promotes oligodendrocyte survival after spinal cord injury. Glia, 51, 73–79.PubMedCrossRefGoogle Scholar
  182. Kiefer, R., Schweitzer, T., Jung, S., Toyka, K. V., & Hartung, H. P. (1998). Sequential expression of transforming growth factor-beta1 by T-cells, macrophages, and microglia in rat spinal cord during autoimmune inflammation. Journal of Neuropathology and Experimental Neurology, 57, 385–395.PubMedCrossRefGoogle Scholar
  183. Kim, B. S., Palma, J. P., Kwon, D., & Fuller, A. C. (2005). Innate immune response induced by Theiler’s murine encephalomyelitis virus infection. Immunologic Research, 31, 1–12.PubMedCrossRefGoogle Scholar
  184. Kirwin, S. J., Dowdell, K. C., Hindinger, C., Feng, N., Bergmann, C. C., Hinton, D. R., et al. (2006). Altered neuroantigen-specific cytokine secretion in a Th2 environment reduces experimental autoimmune encephalomyelitis. Journal of Neuroimmunology, 178, 30–39.PubMedCrossRefGoogle Scholar
  185. Kohji, T., & Matsumoto, Y. (2000). Coexpression of Fas/FasL and Bax on brain and infiltrating T cells in the central nervous system is closely associated with apoptotic cell death during autoimmune encephalomyelitis. Journal of Neuroimmunology, 106, 165–171.PubMedCrossRefGoogle Scholar
  186. Kohm, A. P., Carpentier, P. A., Anger, H. A., & Miller, S. D. (2002). Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. Journal of Immunology, 169, 4712–4716.Google Scholar
  187. Koizumi, S., Shigemoto-Mogami, Y., Nasu-Tada, K., Shinozaki, Y., Ohsawa, K., Tsuda, M., et al. (2007). UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature, 446, 1091–1095.PubMedCrossRefGoogle Scholar
  188. Korner, H., Goodsall, A. L., Lemckert, F. A., Scallon, B. J., Ghrayeb, J., Ford, A. L., et al. (1995). Unimpaired autoreactive T-cell traffic within the central nervous system during tumor necrosis factor receptor-mediated inhibition of experimental autoimmune encephalomyelitis. Proceedings of the National Academy of Sciences of the United States of America, 92, 11066–11070.PubMedCrossRefGoogle Scholar
  189. Kotter, M. R., Li, W. W., Zhao, C., & Franklin, R. J. (2006). Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. Journal of Neuroscience, 26, 328–332.PubMedCrossRefGoogle Scholar
  190. Kotter, M. R., Setzu, A., Sim, F. J., Van Rooijen, N., & Franklin, R. J. (2001). Macrophage depletion impairs oligodendrocyte remyelination following lysolecithin-induced demyelination. Glia, 35, 204–212.PubMedCrossRefGoogle Scholar
  191. Kotter, M. R., Zhao, C., van Rooijen, N., & Franklin, R. J. (2005). Macrophage-depletion induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expression. Neurobiology of Diseases, 18, 166–175.CrossRefGoogle Scholar
  192. Krady, J. K., Lin, H. W., Liberto, C. M., Basu, A., Kremlev, S. G., & Levison, S. W. (2008). Ciliary neurotrophic factor and interleukin-6 differentially activate microglia. Journal of Neuroscience Research, 86, 1538–1547.PubMedCrossRefGoogle Scholar
  193. Krakowski, M., & Owens, T. (1996). Interferon-gamma confers resistance to experimental allergic encephalomyelitis. European Journal of Immunology, 26, 1641–1646.PubMedCrossRefGoogle Scholar
  194. Kroenke, M. A., Carlson, T. J., Andjelkovic, A. V., & Segal, B. M. (2008). IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. Journal of Experimental Medicine, 205, 1535–1541.PubMedCrossRefGoogle Scholar
  195. Kuroda, Y., & Shimamoto, Y. (1991). Human tumor necrosis factor-alpha augments experimental allergic encephalomyelitis in rats. Journal of Neuroimmunology, 34, 159–164.PubMedCrossRefGoogle Scholar
  196. Kuruvilla, A. P., Shah, R., Hochwald, G. M., Liggitt, H. D., Palladino, M. A., & Thorbecke, G. J. (1991). Protective effect of transforming growth factor beta 1 on experimental autoimmune diseases in mice. Proceedings of the National Academy of Sciences of the United States of America, 88, 2918–2921.PubMedCrossRefGoogle Scholar
  197. Kwidzinski, E., Bunse, J., Aktas, O., Richter, D., Mutlu, L., Zipp, F., et al. (2005). Indolamine 2, 3-dioxygenase is expressed in the CNS and down-regulates autoimmune inflammation. The FASEB Journal, 19, 1347–1349.PubMedGoogle Scholar
  198. Kwidzinski, E., Bunse, J., Kovac, A. D., Ullrich, O., Zipp, F., Nitsch, R., et al. (2003). IDO (indolamine 2, 3-dioxygenase) expression and function in the CNS. Advances in Experimental Medicine and Biology, 527, 113–118.PubMedGoogle Scholar
  199. Labow, M., Shuster, D., Zetterstrom, M., Nunes, P., Terry, R., Cullinan, E. B., et al. (1997). Absence of IL-1 signaling and reduced inflammatory response in IL-1 type I receptor-deficient mice. Journal of Immunology, 159, 2452–2461.Google Scholar
  200. Lalancette-Hebert, M., Gowing, G., Simard, A., Weng, Y. C., & Kriz, J. (2007). Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. Journal of Neuroscience, 27, 2596–2605.PubMedCrossRefGoogle Scholar
  201. Lalive, P. H., Paglinawan, R., Biollaz, G., Kappos, E. A., Leone, D. P., Malipiero, U., et al. (2005). TGF-beta-treated microglia induce oligodendrocyte precursor cell chemotaxis through the HGF-c-Met pathway. European Journal of Immunology, 35, 727–737.PubMedCrossRefGoogle Scholar
  202. Langrish, C. L., Chen, Y., Blumenschein, W. M., Mattson, J., Basham, B., Sedgwick, J. D., et al. (2005). IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. Journal of Experimental Medicine, 201, 233–240.PubMedCrossRefGoogle Scholar
  203. Langrish, C. L., McKenzie, B. S., Wilson, N. J., de Waal Malefyt, R., Kastelein, R. A., & Cua, D. J. (2004). IL-12 and IL-23: Master regulators of innate and adaptive immunity. Immunological Reviews, 202, 96–105.PubMedCrossRefGoogle Scholar
  204. Lassmann, H. (2008). Mechanisms of inflammation induced tissue injury in multiple sclerosis. Journal of the Neurological Sciences, 274, 45–47.PubMedCrossRefGoogle Scholar
  205. Lassmann, H., Bruck, W., Lucchinetti, C., & Rodriguez, M. (1997). Remyelination in multiple sclerosis. Multiple Sclerosis, 3, 133–136.PubMedCrossRefGoogle Scholar
  206. Ledeboer, A., Breve, J. J., Poole, S., Tilders, F. J., & Van Dam, A. M. (2000). Interleukin-10, interleukin-4, and transforming growth factor-beta differentially regulate lipopolysaccharide-induced production of pro-inflammatory cytokines and nitric oxide in co-cultures of rat astroglial and microglial cells. Glia, 30, 134–142.PubMedCrossRefGoogle Scholar
  207. Ledeboer, A., Breve, J. J., Wierinckx, A., van der Jagt, S., Bristow, A. F., Leysen, J. E., et al. (2002). Expression and regulation of interleukin-10 and interleukin-10 receptor in rat astroglial and microglial cells. European Journal of Neuroscience, 16, 1175–1185.PubMedCrossRefGoogle Scholar
  208. Lee, W. P., Liao, Y., Robinson, D., Kung, H. J., Liu, E. T., & Hung, M. C. (1999). Axl-gas6 interaction counteracts E1A-mediated cell growth suppression and proapoptotic activity. Molecular and Cellular Biology, 19, 8075–8082.PubMedGoogle Scholar
  209. Leonard, J. P., Waldburger, K. E., & Goldman, S. J. (1995). Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. Journal of Experimental Medicine, 181, 381–386.PubMedCrossRefGoogle Scholar
  210. Li, J., Baud, O., Vartanian, T., Volpe, J. J., & Rosenberg, P. A. (2005a). Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes. Proceedings of the National Academy of Sciences of the United States of America, 102, 9936–9941.PubMedCrossRefGoogle Scholar
  211. Li, Y., Chu, N., Hu, A., Gran, B., Rostami, A., & Zhang, G. X. (2007). Increased IL-23p19 expression in multiple sclerosis lesions and its induction in microglia. Brain, 130, 490–501.PubMedCrossRefGoogle Scholar
  212. Li, Y., Chu, N., Rostami, A., & Zhang, G. X. (2006a). Dendritic cells transduced with SOCS-3 exhibit a tolerogenic/DC2 phenotype that directs type 2 Th cell differentiation in vitro and in vivo. Journal of Immunology, 177, 1679–1688.Google Scholar
  213. Li, J., Gran, B., Zhang, G. X., Rostami, A., & Kamoun, M. (2005b). IL-27 subunits and its receptor (WSX-1) mRNAs are markedly up-regulated in inflammatory cells in the CNS during experimental autoimmune encephalomyelitis. Journal of the Neurological Sciences, 232, 3–9.PubMedCrossRefGoogle Scholar
  214. Li, W., Maeda, Y., Ming, X., Cook, S., Chapin, J., Husar, W., et al. (2002). Apoptotic death following Fas activation in human oligodendrocyte hybrid cultures. Journal of Neuroscience Research, 69, 189–196.PubMedCrossRefGoogle Scholar
  215. Li, M. O., Wan, Y. Y., Sanjabi, S., Robertson, A. K., & Flavell, R. A. (2006b). Transforming growth factor-beta regulation of immune responses. Annual Review of Immunology, 24, 99–146.PubMedCrossRefGoogle Scholar
  216. Li, M., Zhou, Y., Feng, G., & Su, S. B. (2009). The critical role of Toll-like receptor signaling pathways in the induction and progression of autoimmune diseases. Current Molecular Medicine, 9, 365–374.PubMedCrossRefGoogle Scholar
  217. Lin, W., Kemper, A., Dupree, J. L., Harding, H. P., Ron, D., & Popko, B. (2006). Interferon-gamma inhibits central nervous system remyelination through a process modulated by endoplasmic reticulum stress. Brain, 129, 1306–1318.PubMedCrossRefGoogle Scholar
  218. Lin, H. W., & Levison, S. W. (2009). Context-dependent IL-6 potentiation of interferon- gamma-induced IL-12 secretion and CD40 expression in murine microglia. Journal of Neurochemistry, 111, 808–818.PubMedCrossRefGoogle Scholar
  219. Lin, M. W., Tsao, L. T., Chang, L. C., Chen, Y. L., Huang, L. J., Kuo, S. C., et al. (2007). Inhibition of lipopolysaccharide-stimulated NO production by a novel synthetic compound CYL-4d in RAW 264.7 macrophages involving the blockade of MEK4/JNK/AP-1 pathway. Biochemical Pharmacology, 73, 1796–1806.PubMedCrossRefGoogle Scholar
  220. Lipton, H. L. (1975). Theiler’s virus infection in mice: An unusual biphasic disease process leading to demyelination. Infection and Immunity, 11, 1147–1155.PubMedGoogle Scholar
  221. Lipton, H. L., Kumar, A. S., & Trottier, M. (2005). Theiler’s virus persistence in the central nervous system of mice is associated with continuous viral replication and a difference in outcome of infection of infiltrating macrophages versus oligodendrocytes. Virus Research, 111, 214–223.PubMedCrossRefGoogle Scholar
  222. Liu, J., Marino, M. W., Wong, G., Grail, D., Dunn, A., Bettadapura, J., et al. (1998). TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination. Nature Medicine, 4, 78–83.PubMedCrossRefGoogle Scholar
  223. Liu, Y., Teige, I., Ericsson, I., Navikas, V., and Issazadeh-Navikas, S. (2010) Suppression of EAE by oral tolerance is independent of endogenous IFN-beta whereas treatment with recombinant IFN-beta ameliorates EAE. Immunol Cell Biol. Jan 12 (Epub ahead of print).Google Scholar
  224. Lodge, P. A., & Sriram, S. (1996). Regulation of microglial activation by TGF-beta, IL-10, and CSF-1. Journal of Leukocyte Biology, 60, 502–508.PubMedGoogle Scholar
  225. Longbrake, E. E., & Racke, M. K. (2009). Why did IL-12/IL-23 antibody therapy fail in multiple sclerosis? Expert Review of Neurotherapeutics, 9, 319–321.PubMedCrossRefGoogle Scholar
  226. Loughlin, A. J., Woodroofe, M. N., & Cuzner, M. L. (1993). Modulation of interferon-gamma-induced major histocompatibility complex class II and Fc receptor expression on isolated microglia by transforming growth factor-beta 1, interleukin-4, noradrenaline and glucocorticoids. Immunology, 79, 125–130.PubMedGoogle Scholar
  227. Louis, J. C., Magal, E., Takayama, S., & Varon, S. (1993). CNTF protection of oligodendrocytes against natural and tumor necrosis factor-induced death. Science, 259, 689–692.PubMedCrossRefGoogle Scholar
  228. Lovas, G., Szilagyi, N., Majtenyi, K., Palkovits, M., & Komoly, S. (2000). Axonal changes in chronic demyelinated cervical spinal cord plaques. Brain, 123(Pt 2), 308–317.PubMedCrossRefGoogle Scholar
  229. Lowenstein, C. J., Alley, E. W., Raval, P., Snowman, A. M., Snyder, S. H., Russell, S. W., et al. (1993). Macrophage nitric oxide synthase gene: Two upstream regions mediate induction by interferon gamma and lipopolysaccharide. Proceedings of the National Academy of Sciences of the United States of America, 90, 9730–9734.PubMedCrossRefGoogle Scholar
  230. Lucas, S., Ghilardi, N., Li, J., & de Sauvage, F. J. (2003). IL-27 regulates IL-12 responsiveness of naive CD4 + T cells through Stat1-dependent and -independent mechanisms. Proceedings of the National Academy of Sciences of the United States of America, 100, 15047–15052.PubMedCrossRefGoogle Scholar
  231. Lucchinetti, C., Bruck, W., Parisi, J., Scheithauer, B., Rodriguez, M., & Lassmann, H. (1999). A quantitative analysis of oligodendrocytes in multiple sclerosis lesions. A study of 113 cases. Brain, 122(Pt 12), 2279–2295.PubMedCrossRefGoogle Scholar
  232. Lucchinetti, C., Bruck, W., Parisi, J., Scheithauer, B., Rodriguez, M., & Lassmann, H. (2000). Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination. Annals of Neurology, 47, 707–717.PubMedCrossRefGoogle Scholar
  233. Lucchinetti, C. F., Bruck, W., Rodriguez, M., & Lassmann, H. (1996). Distinct patterns of multiple sclerosis pathology indicates heterogeneity on pathogenesis. Brain Pathology, 6, 259–274.PubMedCrossRefGoogle Scholar
  234. Luo, J., Ho, P. P., Buckwalter, M. S., Hsu, T., Lee, L. Y., Zhang, H., et al. (2007). Glia-dependent TGF-beta signaling, acting independently of the TH17 pathway, is critical for initiation of murine autoimmune encephalomyelitis. Journal of Clinical Investigation, 117, 3306–3315.PubMedCrossRefGoogle Scholar
  235. Magnus, T., Chan, A., Linker, R. A., Toyka, K. V., & Gold, R. (2002a). Astrocytes are less efficient in the removal of apoptotic lymphocytes than microglia cells: Implications for the role of glial cells in the inflamed central nervous system. Journal of Neuropathology and Experimental Neurology, 61, 760–766.PubMedGoogle Scholar
  236. Magnus, T., Chan, A., Savill, J., Toyka, K. V., & Gold, R. (2002b). Phagocytotic removal of apoptotic, inflammatory lymphocytes in the central nervous system by microglia and its functional implications. Journal of Neuroimmunology, 130, 1–9.PubMedCrossRefGoogle Scholar
  237. Maimone, D., Gregory, S., Arnason, B. G., & Reder, A. T. (1991). Cytokine levels in the cerebrospinal fluid and serum of patients with multiple sclerosis. Journal of Neuroimmunology, 32, 67–74.PubMedCrossRefGoogle Scholar
  238. Maimone, D., Guazzi, G. C., & Annunziata, P. (1997). IL-6 detection in multiple sclerosis brain. Journal of the Neurological Sciences, 146, 59–65.PubMedCrossRefGoogle Scholar
  239. Makwana, M., Jones, L. L., Cuthill, D., Heuer, H., Bohatschek, M., Hristova, M., et al. (2007). Endogenous transforming growth factor beta 1 suppresses inflammation and promotes survival in adult CNS. Journal of Neuroscience, 27, 11201–11213.PubMedCrossRefGoogle Scholar
  240. Malipiero, U. V., Frei, K., & Fontana, A. (1990). Production of hemopoietic colony-stimulating factors by astrocytes. Journal of Immunology, 144, 3816–3821.Google Scholar
  241. Mana, P., Linares, D., Fordham, S., Staykova, M., & Willenborg, D. (2006). Deleterious role of IFNgamma in a toxic model of central nervous system demyelination. American Journal of Pathology, 168, 1464–1473.PubMedCrossRefGoogle Scholar
  242. Manetti, R., Parronchi, P., Giudizi, M. G., Piccinni, M. P., Maggi, E., Trinchieri, G., et al. (1993). Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. Journal of Experimental Medicine, 177, 1199–1204.PubMedCrossRefGoogle Scholar
  243. Mangan, P. R., Harrington, L. E., O’Quinn, D. B., Helms, W. S., Bullard, D. C., Elson, C. O., et al. (2006). Transforming growth factor-beta induces development of the T(H)17 lineage. Nature, 441, 231–234.PubMedCrossRefGoogle Scholar
  244. Mannie, M. D., Abbott, D. J., & Blanchfield, J. L. (2009). Experimental autoimmune encephalomyelitis in Lewis rats: IFN-beta acts as a tolerogenic adjuvant for induction of neuroantigen-dependent tolerance. Journal of Immunology, 182, 5331–5341.CrossRefGoogle Scholar
  245. Marik, C., Felts, P. A., Bauer, J., Lassmann, H., & Smith, K. J. (2007). Lesion genesis in a subset of patients with multiple sclerosis: A role for innate immunity? Brain, 130, 2800–2815.PubMedCrossRefGoogle Scholar
  246. Markowitz, C. E. (2007). Interferon-beta: Mechanism of action and dosing issues. Neurology, 68, S8–S11.PubMedCrossRefGoogle Scholar
  247. Marriott, M. P., Emery, B., Cate, H. S., Binder, M. D., Kemper, D., Wu, Q., et al. (2008). Leukemia inhibitory factor signaling modulates both central nervous system demyelination and myelin repair. Glia, 56, 686–698.PubMedCrossRefGoogle Scholar
  248. Martin, D., Near, S. L., Bendele, A., & Russell, D. A. (1995). Inhibition of tumor necrosis factor is protective against neurologic dysfunction after active immunization of Lewis rats with myelin basic protein. Experimental Neurology, 131, 221–228.PubMedCrossRefGoogle Scholar
  249. Marusic, S., Miyashiro, J. S., Douhan, J., 3rd, Konz, R. F., Xuan, D., Pelker, J. W., et al. (2002). Local delivery of granulocyte macrophage colony-stimulating factor by retrovirally transduced antigen-specific T cells leads to severe, chronic experimental autoimmune encephalomyelitis in mice. Neuroscience Letters, 332, 185–189.PubMedCrossRefGoogle Scholar
  250. Mason, J. L., Suzuki, K., Chaplin, D. D., & Matsushima, G. K. (2001). Interleukin-1beta promotes repair of the CNS. Journal of Neuroscience, 21, 7046–7052.PubMedGoogle Scholar
  251. Mason, J. L., Xuan, S., Dragatsis, I., Efstratiadis, A., & Goldman, J. E. (2003). Insulin-like growth factor (IGF) signaling through type 1 IGF receptor plays an important role in remyelination. Journal of Neuroscience, 23, 7710–7718.PubMedGoogle Scholar
  252. Matthews, A. E., Weiss, S. R., & Paterson, Y. (2002). Murine hepatitis virus—A model for virus-induced CNS demyelination. Journal of Neurovirology, 8, 76–85.PubMedCrossRefGoogle Scholar
  253. McGuinness, M. C., Powers, J. M., Bias, W. B., Schmeckpeper, B. J., Segal, A. H., Gowda, V. C., et al. (1997). Human leukocyte antigens and cytokine expression in cerebral inflammatory demyelinative lesions of X-linked adrenoleukodystrophy and multiple sclerosis. Journal of Neuroimmunology, 75, 174–182.PubMedCrossRefGoogle Scholar
  254. McMahan, C. J., Slack, J. L., Mosley, B., Cosman, D., Lupton, S. D., Brunton, L. L., et al. (1991). A novel IL-1 receptor, cloned from B cells by mammalian expression, is expressed in many cell types. EMBO Journal, 10, 2821–2832.PubMedGoogle Scholar
  255. McMahon, E. J., Bailey, S. L., Castenada, C. V., Waldner, H., & Miller, S. D. (2005). Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis. Nature Medicine, 11, 335–339.PubMedCrossRefGoogle Scholar
  256. McMahon, E. J., Suzuki, K., & Matsushima, G. K. (2002). Peripheral macrophage recruitment in cuprizone-induced CNS demyelination despite an intact blood-brain barrier. Journal of Neuroimmunology, 130, 32–45.PubMedCrossRefGoogle Scholar
  257. McQualter, J. L., Darwiche, R., Ewing, C., Onuki, M., Kay, T. W., Hamilton, J. A., et al. (2001). Granulocyte macrophage colony-stimulating factor: A new putative therapeutic target in multiple sclerosis. Journal of Experimental Medicine, 194, 873–882.PubMedCrossRefGoogle Scholar
  258. Melaragno, M. G., Cavet, M. E., Yan, C., Tai, L. K., Jin, Z. G., Haendeler, J., et al. (2004). Gas6 inhibits apoptosis in vascular smooth muscle: Role of Axl kinase and Akt. Journal of Molecular and Cellular Cardiology, 37, 881–887.PubMedCrossRefGoogle Scholar
  259. Merrill, J. E. (1991). Effects of interleukin-1 and tumor necrosis factor-alpha on astrocytes, microglia, oligodendrocytes, and glial precursors in vitro. Developmental Neuroscience, 13, 130–137.PubMedCrossRefGoogle Scholar
  260. Miller, A., Lider, O., Roberts, A. B., Sporn, M. B., & Weiner, H. L. (1992). Suppressor T cells generated by oral tolerization to myelin basic protein suppress both in vitro and in vivo immune responses by the release of transforming growth factor beta after antigen-specific triggering. Proceedings of the National Academy of Sciences of the United States of America, 89, 421–425.PubMedCrossRefGoogle Scholar
  261. Miller, S. D., Vanderlugt, C. L., Begolka, W. S., Pao, W., Yauch, R. L., Neville, K. L., et al. (1997). Persistent infection with Theiler’s virus leads to CNS autoimmunity via epitope spreading. Nature Medicine, 3, 1133–1136.PubMedCrossRefGoogle Scholar
  262. Mirshafiey, A., & Mohsenzadegan, M. (2009). TGF-beta as a promising option in the treatment of multiple sclerosis. Neuropharmacology, 56, 929–936.PubMedCrossRefGoogle Scholar
  263. Mitrasinovic, O. M., Perez, G. V., Zhao, F., Lee, Y. L., Poon, C., & Murphy, G. M., Jr. (2001). Overexpression of macrophage colony-stimulating factor receptor on microglial cells induces an inflammatory response. Journal of Biological Chemistry, 276, 30142–30149.PubMedCrossRefGoogle Scholar
  264. Mitrasinovic, O. M., Vincent, V. A., Simsek, D., & Murphy, G. M., Jr. (2003). Macrophage colony stimulating factor promotes phagocytosis by murine microglia. Neuroscience Letters, 344, 185–188.PubMedCrossRefGoogle Scholar
  265. Miyanishi, M., Tada, K., Koike, M., Uchiyama, Y., Kitamura, T., & Nagata, S. (2007). Identification of Tim4 as a phosphatidylserine receptor. Nature, 450, 435–439.PubMedCrossRefGoogle Scholar
  266. Mizuno, T., Sawada, M., Marunouchi, T., & Suzumura, A. (1994). Production of interleukin-10 by mouse glial cells in culture. Biochemical and Biophysical Research Communications, 205, 1907–1915.PubMedCrossRefGoogle Scholar
  267. Mondal, S., Roy, A., & Pahan, K. (2009). Functional blocking monoclonal antibodies against IL-12p40 homodimer inhibit adoptive transfer of experimental allergic encephalomyelitis. Journal of Immunology, 182, 5013–5023.CrossRefGoogle Scholar
  268. Moore, K. W., de Waal Malefyt, R., Coffman, R. L., & O’Garra, A. (2001). Interleukin-10 and the interleukin-10 receptor. Annual Review of Immunology, 19, 683–765.PubMedCrossRefGoogle Scholar
  269. Morell, P., Barrett, C. V., Mason, J. L., Toews, A. D., Hostettler, J. D., Knapp, G. W., et al. (1998). Gene expression in brain during cuprizone-induced demyelination and remyelination. Molecular and Cellular Neurosciences, 12, 220–227.PubMedCrossRefGoogle Scholar
  270. Morishima, N., Mizoguchi, I., Takeda, K., Mizuguchi, J., & Yoshimoto, T. (2009). TGF-beta is necessary for induction of IL-23R and Th17 differentiation by IL-6 and IL-23. Biochemical and Biophysical Research Communications, 386, 105–110.PubMedCrossRefGoogle Scholar
  271. Mosmann, T. R., & Coffman, R. L. (1989). TH1 and TH2 cells: Different patterns of lymphokine secretion lead to different functional properties. Annual Review of Immunology, 7, 145–173.PubMedCrossRefGoogle Scholar
  272. Mosser, D. M., & Zhang, X. (2008). Interleukin-10: New perspectives on an old cytokine. Immunological Reviews, 226, 205–218.PubMedCrossRefGoogle Scholar
  273. MS/MRI Analysis Group. (1999). TNF neutralization in MS: Results of a randomized, placebo-controlled multicenter study. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Neurology, 53, 457–465.Google Scholar
  274. Mujtaba, M. G., Flowers, L. O., Patel, C. B., Patel, R. A., Haider, M. I., & Johnson, H. M. (2005). Treatment of mice with the suppressor of cytokine signaling-1 mimetic peptide, tyrosine kinase inhibitor peptide, prevents development of the acute form of experimental allergic encephalomyelitis and induces stable remission in the chronic. Journal of Immunology, 175, 5077–5086.Google Scholar
  275. Murray, P. J. (2006). Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response. Current Opinion in Pharmacology, 6, 379–386.PubMedCrossRefGoogle Scholar
  276. Nakamura, Y. (2002). Regulating factors for microglial activation. Biological and Pharmaceutical Bulletin, 25, 945–953.PubMedCrossRefGoogle Scholar
  277. Nakano, T., Ishimoto, Y., Kishino, J., Umeda, M., Inoue, K., Nagata, K., et al. (1997). Cell adhesion to phosphatidylserine mediated by a product of growth arrest-specific gene 6. Journal of Biological Chemistry, 272, 29411–29414.PubMedCrossRefGoogle Scholar
  278. Nakayama, T., & Yamashita, M. (2008). Initiation and maintenance of Th2 cell identity. Current Opinion in Immunology, 20, 265–271.PubMedCrossRefGoogle Scholar
  279. Navikas, V., Matusevicius, D., Soderstrom, M., Fredrikson, S., Kivisakk, P., Ljungdahl, A., et al. (1996). Increased interleukin-6 mRNA expression in blood and cerebrospinal fluid mononuclear cells in multiple sclerosis. Journal of Neuroimmunology, 64, 63–69.PubMedCrossRefGoogle Scholar
  280. Neumann, H., Kotter, M. R., & Franklin, R. J. (2009). Debris clearance by microglia: An essential link between degeneration and regeneration. Brain, 132, 288–295.PubMedCrossRefGoogle Scholar
  281. Nguyen, V. T., & Benveniste, E. N. (2000). IL-4-activated STAT-6 inhibits IFN-gamma-induced CD40 gene expression in macrophages/microglia. Journal of Immunology, 165, 6235–6243.Google Scholar
  282. Nicoletti, F., Di Marco, R., Patti, F., Reggio, E., Nicoletti, A., Zaccone, P., et al. (1998). Blood levels of transforming growth factor-beta 1 (TGF-beta1) are elevated in both relapsing remitting and chronic progressive multiple sclerosis (MS) patients and are further augmented by treatment with interferon-beta 1b (IFN-beta1b). Clinical and Experimental Immunology, 113, 96–99.PubMedCrossRefGoogle Scholar
  283. Nishiyama, A., Yu, M., Drazba, J. A., & Tuohy, V. K. (1997). Normal and reactive NG2 + glial cells are distinct from resting and activated microglia. Journal of Neuroscience Research, 48, 299–312.PubMedCrossRefGoogle Scholar
  284. Nowak, E. C., Weaver, C. T., Turner, H., Begum-Haque, S., Becher, B., Schreiner, B., et al. (2009). IL-9 as a mediator of Th17-driven inflammatory disease. Journal of Experimental Medicine, 206, 1653–1660.PubMedCrossRefGoogle Scholar
  285. O’Brien, K., Fitzgerald, D. C., Naiken, K., Alugupalli, K. R., Rostami, A. M., & Gran, B. (2008). Role of the innate immune system in autoimmune inflammatory demyelination. Current Medicinal Chemistry, 15, 1105–1115.PubMedCrossRefGoogle Scholar
  286. O’Connor, R. A., Prendergast, C. T., Sabatos, C. A., Lau, C. W., Leech, M. D., Wraith, D. C., et al. (2008). Cutting edge: Th1 cells facilitate the entry of Th17 cells to the central nervous system during experimental autoimmune encephalomyelitis. Journal of Immunology, 181, 3750–3754.Google Scholar
  287. O’Garra, A., & Arai, N. (2000). The molecular basis of T helper 1 and T helper 2 cell differentiation. Trends in Cell Biology, 10, 542–550.PubMedCrossRefGoogle Scholar
  288. O’Keefe, G. M., Nguyen, V. T., & Benveniste, E. N. (1999). Class II transactivator and class II MHC gene expression in microglia: Modulation by the cytokines TGF-beta, IL-4, IL-13 and IL-10. European Journal of Immunology, 29, 1275–1285.PubMedCrossRefGoogle Scholar
  289. O’Keefe, G. M., Nguyen, V. T., & Benveniste, E. N. (2002). Regulation and function of class II major histocompatibility complex, CD40, and B7 expression in macrophages and microglia: Implications in neurological diseases. Journal of Neurovirology, 8, 496–512.PubMedCrossRefGoogle Scholar
  290. O’Keefe, G. M., Nguyen, V. T., Ping Tang, L. L., & Benveniste, E. N. (2001). IFN-gamma regulation of class II transactivator promoter IV in macrophages and microglia: Involvement of the suppressors of cytokine signaling-1 protein. Journal of Immunology, 166, 2260–2269.Google Scholar
  291. O’Neill, L. A., & Greene, C. (1998). Signal transduction pathways activated by the IL-1 receptor family: Ancient signaling machinery in mammals, insects, and plants. Journal of Leukocyte Biology, 63, 650–657.PubMedGoogle Scholar
  292. O’Shea, J. J., Ma, A., & Lipsky, P. (2002). Cytokines and autoimmunity. Nature Reviews Immunology, 2, 37–45.PubMedCrossRefGoogle Scholar
  293. Okuda, Y., Sakoda, S., Bernard, C. C., Fujimura, H., Saeki, Y., Kishimoto, T., et al. (1998). IL-6-deficient mice are resistant to the induction of experimental autoimmune encephalomyelitis provoked by myelin oligodendrocyte glycoprotein. International Immunology, 10, 703–708.PubMedCrossRefGoogle Scholar
  294. Okuda, Y., Sakoda, S., Fujimura, H., Saeki, Y., Kishimoto, T., & Yanagihara, T. (1999). IL-6 plays a crucial role in the induction phase of myelin oligodendrocyte glucoprotein 35–55 induced experimental autoimmune encephalomyelitis. Journal of Neuroimmunology, 101, 188–196.PubMedCrossRefGoogle Scholar
  295. Oleszak, E. L., Chang, J. R., Friedman, H., Katsetos, C. D., & Platsoucas, C. D. (2004). Theiler’s virus infection: A model for multiple sclerosis. Clinical Microbiology Reviews, 17, 174–207.PubMedCrossRefGoogle Scholar
  296. Pace, L., Rizzo, S., Palombi, C., Brombacher, F., & Doria, G. (2006). Cutting edge: IL-4-induced protection of CD4 + CD25- Th cells from CD4 + CD25 + regulatory T cell-mediated suppression. Journal of Immunology, 176, 3900–3904.Google Scholar
  297. Pahan, K., Sheikh, F. G., Liu, X., Hilger, S., McKinney, M., & Petro, T. M. (2001). Induction of nitric-oxide synthase and activation of NF-kappaB by interleukin-12 p40 in microglial cells. Journal of Biological Chemistry, 276, 7899–7905.PubMedCrossRefGoogle Scholar
  298. Panitch, H. S., Hirsch, R. L., Haley, A. S., & Johnson, K. P. (1987). Exacerbations of multiple sclerosis in patients treated with gamma interferon. Lancet, 1, 893–895.PubMedCrossRefGoogle Scholar
  299. Parham, C., Chirica, M., Timans, J., Vaisberg, E., Travis, M., Cheung, J., et al. (2002). A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. Journal of Immunology, 168, 5699–5708.Google Scholar
  300. Pasquini, L. A., Calatayud, C. A., Bertone Una, A. L., Millet, V., Pasquini, J. M., & Soto, E. F. (2007). The neurotoxic effect of cuprizone on oligodendrocytes depends on the presence of pro-inflammatory cytokines secreted by microglia. Neurochemical Research, 32, 279–292.PubMedCrossRefGoogle Scholar
  301. Patani, R., Balaratnam, M., Vora, A., & Reynolds, R. (2007). Remyelination can be extensive in multiple sclerosis despite a long disease course. Neuropathology and Applied Neurobiology, 33, 277–287.PubMedCrossRefGoogle Scholar
  302. Patrikios, P., Stadelmann, C., Kutzelnigg, A., Rauschka, H., Schmidbauer, M., Laursen, H., et al. (2006). Remyelination is extensive in a subset of multiple sclerosis patients. Brain, 129, 3165–3172.PubMedCrossRefGoogle Scholar
  303. Paty, D. W., & Li, D. K. (1993). Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Neurology, 43, 662–667.PubMedGoogle Scholar
  304. Pender, M. P. (1999). Activation-induced apoptosis of autoreactive and alloreactive T lymphocytes in the target organ as a major mechanism of tolerance. Immunology and Cell Biology, 77, 216–223.PubMedCrossRefGoogle Scholar
  305. Pender, M. P., Nguyen, K. B., McCombe, P. A., & Kerr, J. F. (1991). Apoptosis in the nervous system in experimental allergic encephalomyelitis. Journal of the Neurological Sciences, 104, 81–87.PubMedCrossRefGoogle Scholar
  306. Pestka, S., Krause, C. D., & Walter, M. R. (2004). Interferons, interferon-like cytokines, and their receptors. Immunological Reviews, 202, 8–32.PubMedCrossRefGoogle Scholar
  307. Peterson, J. W., Bo, L., Mork, S., Chang, A., Ransohoff, R. M., & Trapp, B. D. (2002). VCAM-1-positive microglia target oligodendrocytes at the border of multiple sclerosis lesions. Journal of Neuropathology and Experimental Neurology, 61, 539–546.PubMedGoogle Scholar
  308. Pfeffer, K., Matsuyama, T., Kundig, T. M., Wakeham, A., Kishihara, K., Shahinian, A., et al. (1993). Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell, 73, 457–467.PubMedCrossRefGoogle Scholar
  309. Piccio, L., Buonsanti, C., Mariani, M., Cella, M., Gilfillan, S., Cross, A. H., et al. (2007). Blockade of TREM-2 exacerbates experimental autoimmune encephalomyelitis. European Journal of Immunology, 37, 1290–1301.PubMedCrossRefGoogle Scholar
  310. Piccirillo, C. A., & Thornton, A. M. (2004). Cornerstone of peripheral tolerance: Naturally occurring CD4+CD25+ regulatory T cells. Trends in Immunology, 25, 374–380.PubMedCrossRefGoogle Scholar
  311. Platten, M., Ho, P. P., Youssef, S., Fontoura, P., Garren, H., Hur, E. M., et al. (2005). Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite. Science, 310, 850–855.PubMedCrossRefGoogle Scholar
  312. Ponomarev, E. D., Maresz, K., Tan, Y., & Dittel, B. N. (2007a). CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. Journal of Neuroscience, 27, 10714–10721.PubMedCrossRefGoogle Scholar
  313. Ponomarev, E. D., Shriver, L. P., Maresz, K., Pedras-Vasconcelos, J., Verthelyi, D., & Dittel, B. N. (2007b). GM-CSF production by autoreactive T cells is required for the activation of microglial cells and the onset of experimental autoimmune encephalomyelitis. Journal of Immunology, 178, 39–48.Google Scholar
  314. Popko, B., & Baerwald, K. D. (1999). Oligodendroglial response to the immune cytokine interferon gamma. Neurochemical Research, 24, 331–338.PubMedCrossRefGoogle Scholar
  315. Popovic, N., Schubart, A., Goetz, B. D., Zhang, S. C., Linington, C., & Duncan, I. D. (2002). Inhibition of autoimmune encephalomyelitis by a tetracycline. Annals of Neurology, 51, 215–223.PubMedCrossRefGoogle Scholar
  316. Prineas, J. W., Barnard, R. O., Kwon, E. E., Sharer, L. R., & Cho, E. S. (1993). Multiple sclerosis: Remyelination of nascent lesions. Annals of Neurology, 33, 137–151.PubMedCrossRefGoogle Scholar
  317. Prineas, J. W., & Graham, J. S. (1981). Multiple sclerosis: Capping of surface immunoglobulin G on macrophages engaged in myelin breakdown. Annals of Neurology, 10, 149–158.PubMedCrossRefGoogle Scholar
  318. Prineas, J. W., Kwon, E. E., Goldenberg, P. Z., Ilyas, A. A., Quarles, R. H., Benjamins, J. A., et al. (1989). Multiple sclerosis. Oligodendrocyte proliferation and differentiation in fresh lesions. Laboratory Investigation, 61, 489–503.PubMedGoogle Scholar
  319. Prinz, M., Schmidt, H., Mildner, A., Knobeloch, K. P., Hanisch, U. K., Raasch, J., et al. (2008). Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system. Immunity, 28, 675–686.PubMedCrossRefGoogle Scholar
  320. Pullen, L. C., Park, S. H., Miller, S. D., Dal Canto, M. C., & Kim, B. S. (1995). Treatment with bacterial LPS renders genetically resistant C57BL/6 mice susceptible to Theiler’s virus-induced demyelinating disease. Journal of Immunology, 155, 4497–4503.Google Scholar
  321. Qian, L., Wei, S. J., Zhang, D., Hu, X., Xu, Z., Wilson, B., et al. (2008). Potent anti-inflammatory and neuroprotective effects of TGF-beta1 are mediated through the inhibition of ERK and p47phox-Ser345 phosphorylation and translocation in microglia. Journal of Immunology, 181, 660–668.Google Scholar
  322. Qin, H., Roberts, K. L., Niyongere, S. A., Cong, Y., Elson, C. O., & Benveniste, E. N. (2007). Molecular mechanism of lipopolysaccharide-induced SOCS-3 gene expression in macrophages and microglia. Journal of Immunology, 179, 5966–5976.Google Scholar
  323. Qin, H., Wilson, C. A., Lee, S. J., & Benveniste, E. N. (2006a). IFN-beta-induced SOCS-1 negatively regulates CD40 gene expression in macrophages and microglia. The FASEB Journal, 20, 985–987.PubMedCrossRefGoogle Scholar
  324. Qin, H., Wilson, C. A., Roberts, K. L., Baker, B. J., Zhao, X., & Benveniste, E. N. (2006b). IL-10 inhibits lipopolysaccharide-induced CD40 gene expression through induction of suppressor of cytokine signaling-3. Journal of Immunology, 177, 7761–7771.Google Scholar
  325. Quintana, A., Muller, M., Frausto, R. F., Ramos, R., Getts, D. R., Sanz, E., et al. (2009). Site-specific production of IL-6 in the central nervous system retargets and enhances the inflammatory response in experimental autoimmune encephalomyelitis. Journal of Immunology, 183, 2079–2088.CrossRefGoogle Scholar
  326. Racke, M. K., Bonomo, A., Scott, D. E., Cannella, B., Levine, A., Raine, C. S., et al. (1994). Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. Journal of Experimental Medicine, 180, 1961–1966.PubMedCrossRefGoogle Scholar
  327. Racke, M. K., Dhib-Jalbut, S., Cannella, B., Albert, P. S., Raine, C. S., & McFarlin, D. E. (1991). Prevention and treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor-beta 1. Journal of Immunology, 146, 3012–3017.Google Scholar
  328. Radu, D. L., Noben-Trauth, N., Hu-Li, J., Paul, W. E., & Bona, C. A. (2000). A targeted mutation in the IL-4Ralpha gene protects mice against autoimmune diabetes. Proceedings of the National Academy of Sciences of the United States of America, 97, 12700–12704.PubMedCrossRefGoogle Scholar
  329. Raine, C. S., & Wu, E. (1993). Multiple sclerosis: Remyelination in acute lesions. Journal of Neuropathology and Experimental Neurology, 52, 199–204.PubMedCrossRefGoogle Scholar
  330. Ransohoff, R. M., & Perry, V. H. (2009). Microglial physiology: Unique stimuli, specialized responses. Annual Review of Immunology, 27, 119–145.PubMedCrossRefGoogle Scholar
  331. Re, F., Belyanskaya, S. L., Riese, R. J., Cipriani, B., Fischer, F. R., Granucci, F., et al. (2002). Granulocyte-macrophage colony-stimulating factor induces an expression program in neonatal microglia that primes them for antigen presentation. Journal of Immunology, 169, 2264–2273.Google Scholar
  332. Rentzos, M., Nikolaou, C., Rombos, A., Voumvourakis, K., Segditsa, I., & Papageorgiou, C. (1996). Tumour necrosis factor alpha is elevated in serum and cerebrospinal fluid in multiple sclerosis and inflammatory neuropathies. Journal of Neurology, 243, 165–170.PubMedCrossRefGoogle Scholar
  333. Rieckmann, P., Albrecht, M., Kitze, B., Weber, T., Tumani, H., Broocks, A., et al. (1995). Tumor necrosis factor-alpha messenger RNA expression in patients with relapsing-remitting multiple sclerosis is associated with disease activity. Annals of Neurology, 37, 82–88.PubMedCrossRefGoogle Scholar
  334. Rothe, J., Lesslauer, W., Lotscher, H., Lang, Y., Koebel, P., Kontgen, F., et al. (1993). Mice lacking the tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature, 364, 798–802.PubMedCrossRefGoogle Scholar
  335. Rothlin, C. V., Ghosh, S., Zuniga, E. I., Oldstone, M. B., & Lemke, G. (2007). TAM receptors are pleiotropic inhibitors of the innate immune response. Cell, 131, 1124–1136.PubMedCrossRefGoogle Scholar
  336. Rothuizen, L. E., Buclin, T., Spertini, F., Trinchard, I., Munafo, A., Buchwalder, P. A., et al. (1999). Influence of interferon beta-1a dose frequency on PBMC cytokine secretion and biological effect markers. Journal of Neuroimmunology, 99, 131–141.PubMedCrossRefGoogle Scholar
  337. Rothwell, N. J., & Luheshi, G. N. (2000). Interleukin 1 in the brain: Biology, pathology and therapeutic target. Trends in Neurosciences, 23, 618–625.PubMedCrossRefGoogle Scholar
  338. Ruddle, N. H., Bergman, C. M., McGrath, K. M., Lingenheld, E. G., Grunnet, M. L., Padula, S. J., et al. (1990). An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis. Journal of Experimental Medicine, 172, 1193–1200.PubMedCrossRefGoogle Scholar
  339. Ruuls, S. R., de Labie, M. C., Weber, K. S., Botman, C. A., Groenestein, R. J., Dijkstra, C. D., et al. (1996). The length of treatment determines whether IFN-beta prevents or aggravates experimental autoimmune encephalomyelitis in Lewis rats. Journal of Immunology, 157, 5721–5731.Google Scholar
  340. Samoilova, E. B., Horton, J. L., Hilliard, B., Liu, T. S., & Chen, Y. (1998). IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: Roles of IL-6 in the activation and differentiation of autoreactive T cells. Journal of Immunology, 161, 6480–6486.Google Scholar
  341. Santambrogio, L., Hochwald, G. M., Saxena, B., Leu, C. H., Martz, J. E., Carlino, J. A., et al. (1993). Studies on the mechanisms by which transforming growth factor-beta (TGF-beta) protects against allergic encephalomyelitis. Antagonism between TGF-beta and tumor necrosis factor. Journal of Immunology, 151, 1116–1127.Google Scholar
  342. Sather, B. D., Treuting, P., Perdue, N., Miazgowicz, M., Fontenot, J. D., Rudensky, A. Y., et al. (2007). Altering the distribution of Foxp3(+) regulatory T cells results in tissue-specific inflammatory disease. Journal of Experimental Medicine, 204, 1335–1347.PubMedCrossRefGoogle Scholar
  343. Schiffenbauer, J., Streit, W. J., Butfiloski, E., LaBow, M., Edwards, C., 3rd, & Moldawer, L. L. (2000). The induction of EAE is only partially dependent on TNF receptor signaling but requires the IL-1 type I receptor. Clinical Immunology, 95, 117–123.PubMedCrossRefGoogle Scholar
  344. Schluesener, H. J., & Lider, O. (1989). Transforming growth factors beta 1 and beta 2: Cytokines with identical immunosuppressive effects and a potential role in the regulation of autoimmune T cell function. Journal of Neuroimmunology, 24, 249–258.PubMedCrossRefGoogle Scholar
  345. Schmidt, H., Raasch, J., Merkler, D., Klinker, F., Krauss, S., Bruck, W., et al. (2009). Type I interferon receptor signalling is induced during demyelination while its function for myelin damage and repair is redundant. Experimental Neurology, 216, 306–311.PubMedCrossRefGoogle Scholar
  346. Schmierer, B., & Hill, C. S. (2007). TGFbeta-SMAD signal transduction: Molecular specificity and functional flexibility. Nat Rev Mol Cell Biol, 8, 970–982.PubMedCrossRefGoogle Scholar
  347. Schmitz, T., & Chew, L. J. (2008). Cytokines and myelination in the central nervous system. Scientific World Journal, 8, 1119–1147.PubMedGoogle Scholar
  348. Schonrock, L. M., Gawlowski, G., & Bruck, W. (2000). Interleukin-6 expression in human multiple sclerosis lesions. Neuroscience Letters, 294, 45–48.PubMedCrossRefGoogle Scholar
  349. Scolding, N., Franklin, R., Stevens, S., Heldin, C. H., Compston, A., & Newcombe, J. (1998). Oligodendrocyte progenitors are present in the normal adult human CNS and in the lesions of multiple sclerosis. Brain, 121(Pt 12), 2221–2228.PubMedCrossRefGoogle Scholar
  350. Scutera, S., Fraone, T., Musso, T., Cappello, P., Rossi, S., Pierobon, D., et al. (2009). Survival and migration of human dendritic cells are regulated by an IFN-alpha-inducible Axl/Gas6 pathway. Journal of Immunology, 183, 3004–3013.CrossRefGoogle Scholar
  351. Sebire, G., Emilie, D., Wallon, C., Hery, C., Devergne, O., Delfraissy, J. F., et al. (1993). In vitro production of IL-6, IL-1 beta, and tumor necrosis factor-alpha by human embryonic microglial and neural cells. Journal of Immunology, 150, 1517–1523.Google Scholar
  352. Segal, B. M., Constantinescu, C. S., Raychaudhuri, A., Kim, L., Fidelus-Gort, R., & Kasper, L. H. (2008). Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: A phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurology, 7, 796–804.PubMedCrossRefGoogle Scholar
  353. Segal, B. M., Dwyer, B. K., & Shevach, E. M. (1998). An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. Journal of Experimental Medicine, 187, 537–546.PubMedCrossRefGoogle Scholar
  354. Selmaj, K. W., & Raine, C. S. (1988). Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro. Annals of Neurology, 23, 339–346.PubMedCrossRefGoogle Scholar
  355. Selmaj, K. W., & Raine, C. S. (1995). Experimental autoimmune encephalomyelitis: Immunotherapy with anti-tumor necrosis factor antibodies and soluble tumor necrosis factor receptors. Neurology, 45, S44–S49.PubMedGoogle Scholar
  356. Selmaj, K., Raine, C. S., & Cross, A. H. (1991). Anti-tumor necrosis factor therapy abrogates autoimmune demyelination. Annals of Neurology, 30, 694–700.PubMedCrossRefGoogle Scholar
  357. Selvaraju, R., Bernasconi, L., Losberger, C., Graber, P., Kadi, L., Avellana-Adalid, V., et al. (2004). Osteopontin is upregulated during in vivo demyelination and remyelination and enhances myelin formation in vitro. Molecular and Cellular Neurosciences, 25, 707–721.PubMedCrossRefGoogle Scholar
  358. Serada, S., Fujimoto, M., Mihara, M., Koike, N., Ohsugi, Y., Nomura, S., et al. (2008). IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis. Proceedings of the National Academy of Sciences of the United States of America, 105, 9041–9046.PubMedCrossRefGoogle Scholar
  359. Setzu, A., Lathia, J. D., Zhao, C., Wells, K., Rao, M. S., Ffrench-Constant, C., et al. (2006). Inflammation stimulates myelination by transplanted oligodendrocyte precursor cells. Glia, 54, 297–303.PubMedCrossRefGoogle Scholar
  360. Shankar, S. L., O’Guin, K., Cammer, M., McMorris, F. A., Stitt, T. N., Basch, R. S., et al. (2003). The growth arrest-specific gene product Gas6 promotes the survival of human oligodendrocytes via a phosphatidylinositol 3-kinase-dependent pathway. Journal of Neuroscience, 23, 4208–4218.PubMedGoogle Scholar
  361. Shankar, S. L., O’Guin, K., Kim, M., Varnum, B., Lemke, G., Brosnan, C. F., et al. (2006). Gas6/Axl signaling activates the phosphatidylinositol 3-kinase/Akt1 survival pathway to protect oligodendrocytes from tumor necrosis factor alpha-induced apoptosis. Journal of Neuroscience, 26, 5638–5648.PubMedCrossRefGoogle Scholar
  362. Sharif, M. N., Sosic, D., Rothlin, C. V., Kelly, E., Lemke, G., Olson, E. N., et al. (2006). Twist mediates suppression of inflammation by type I IFNs and Axl. Journal of Experimental Medicine, 203, 1891–1901.PubMedCrossRefGoogle Scholar
  363. Shaw, M. K., Lorens, J. B., Dhawan, A., DalCanto, R., Tse, H. Y., Tran, A. B., et al. (1997). Local delivery of interleukin 4 by retrovirus-transduced T lymphocytes ameliorates experimental autoimmune encephalomyelitis. Journal of Experimental Medicine, 185, 1711–1714.PubMedCrossRefGoogle Scholar
  364. Sheehan, K. C., Pinckard, J. K., Arthur, C. D., Dehner, L. P., Goeddel, D. V., & Schreiber, R. D. (1995). Monoclonal antibodies specific for murine p55 and p75 tumor necrosis factor receptors: Identification of a novel in vivo role for p75. Journal of Experimental Medicine, 181, 607–617.PubMedCrossRefGoogle Scholar
  365. Shevach, E. M. (2000). Regulatory T cells in autoimmmunity. Annual Review of Immunology, 18, 423–449.PubMedCrossRefGoogle Scholar
  366. Shields, S., Gilson, J., Blakemore, W., & Franklin, R. (2000). Remyelination occurs as extensively but more slowly in old rats compared to young rats following fliotoxin-induced CNS demyelination. Glia, 29, 102.PubMedCrossRefGoogle Scholar
  367. Shinohara, M. L., Kim, J. H., Garcia, V. A., & Cantor, H. (2008). Engagement of the type I interferon receptor on dendritic cells inhibits T helper 17 cell development: Role of intracellular osteopontin. Immunity, 29, 68–78.PubMedCrossRefGoogle Scholar
  368. Shull, M. M., Ormsby, I., Kier, A. B., Pawlowski, S., Diebold, R. J., Yin, M., et al. (1992). Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature, 359, 693–699.PubMedCrossRefGoogle Scholar
  369. Smith, M. E. (1999). Phagocytosis of myelin in demyelinative disease: A review. Neurochemical Research, 24, 261–268.PubMedCrossRefGoogle Scholar
  370. Smith, M. E., van der Maesen, K., & Somera, F. P. (1998). Macrophage and microglial responses to cytokines in vitro: Phagocytic activity, proteolytic enzyme release, and free radical production. Journal of Neuroscience Research, 54, 68–78.PubMedCrossRefGoogle Scholar
  371. Soh, J., Donnelly, R. J., Kotenko, S., Mariano, T. M., Cook, J. R., Wang, N., et al. (1994). Identification and sequence of an accessory factor required for activation of the human interferon gamma receptor. Cell, 76, 793–802.PubMedCrossRefGoogle Scholar
  372. Soldan, S. S., Alvarez Retuerto, A. I., Sicotte, N. L., & Voskuhl, R. R. (2004). Dysregulation of IL-10 and IL-12p40 in secondary progressive multiple sclerosis. Journal of Neuroimmunology, 146, 209–215.PubMedCrossRefGoogle Scholar
  373. Sonobe, Y., Liang, J., Jin, S., Zhang, G., Takeuchi, H., Mizuno, T., et al. (2008). Microglia express a functional receptor for interleukin-23. Biochemical and Biophysical Research Communications, 370, 129–133.PubMedCrossRefGoogle Scholar
  374. Sonobe, Y., Yawata, I., Kawanokuchi, J., Takeuchi, H., Mizuno, T., & Suzumura, A. (2005). Production of IL-27 and other IL-12 family cytokines by microglia and their subpopulations. Brain Research, 1040, 202–207.PubMedCrossRefGoogle Scholar
  375. Sospedra, M., & Martin, R. (2005). Immunology of multiple sclerosis. Annual Review of Immunology, 23, 683–747.PubMedCrossRefGoogle Scholar
  376. Staykova, M. A., Berven, L. A., Cowden, W. B., Willenborg, D. O., & Crouch, M. F. (2003). Nitric oxide induces polarization of actin in encephalitogenic T cells and inhibits their in vitro trans-endothelial migration in a p70S6 kinase-independent manner. The FASEB Journal, 17, 1337–1339.PubMedGoogle Scholar
  377. Steinman, L., & Zamvil, S. S. (2005). Virtues and pitfalls of EAE for the development of therapies for multiple sclerosis. Trends in Immunology, 26, 565–571.PubMedCrossRefGoogle Scholar
  378. Stevens, D. B., Gould, K. E., & Swanborg, R. H. (1994). Transforming growth factor-beta 1 inhibits tumor necrosis factor-alpha/lymphotoxin production and adoptive transfer of disease by effector cells of autoimmune encephalomyelitis. Journal of Neuroimmunology, 51, 77–83.PubMedCrossRefGoogle Scholar
  379. Stumhofer, J. S., Laurence, A., Wilson, E. H., Huang, E., Tato, C. M., Johnson, L. M., et al. (2006). Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nature Immunology, 7, 937–945.PubMedCrossRefGoogle Scholar
  380. Sugiura, S., Lahav, R., Han, J., Kou, S. Y., Banner, L. R., de Pablo, F., et al. (2000). Leukaemia inhibitory factor is required for normal inflammatory responses to injury in the peripheral and central nervous systems in vivo and is chemotactic for macrophages in vitro. European Journal of Neuroscience, 12, 457–466.PubMedCrossRefGoogle Scholar
  381. Suzumura, A., Sawada, M., Yamamoto, H., & Marunouchi, T. (1993). Transforming growth factor-beta suppresses activation and proliferation of microglia in vitro. Journal of Immunology, 151, 2150–2158.Google Scholar
  382. Takahashi, K., Prinz, M., Stagi, M., Chechneva, O., & Neumann, H. (2007). TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Medicine, 4, e124.PubMedCrossRefGoogle Scholar
  383. Takeda, A., Hamano, S., Yamanaka, A., Hanada, T., Ishibashi, T., Mak, T. W., et al. (2003). Cutting edge: Role of IL-27/WSX-1 signaling for induction of T-bet through activation of STAT1 during initial Th1 commitment. Journal of Immunology, 170, 4886–4890.Google Scholar
  384. Takeuchi, A., Miyaishi, O., Kiuchi, K., & Isobe, K. (2001). Macrophage colony-stimulating factor is expressed in neuron and microglia after focal brain injury. Journal of Neuroscience Research, 65, 38–44.PubMedCrossRefGoogle Scholar
  385. Taniguchi, T., & Takaoka, A. (2001). A weak signal for strong responses: Interferon-alpha/beta revisited. Nature Reviews. Molecular Cell Biology, 2, 378–386.PubMedCrossRefGoogle Scholar
  386. Tansey, M. G., & Wyss-Coray, T. (2008). Cytokines in CNS Inflammation and Disease. In T. E. Lane, M. Carson, C. Bergman, & T. Wyss-Coray (Eds.), Central nervous system diseases and inflammation (pp. 59–106). Heidelberg: Springer.CrossRefGoogle Scholar
  387. Tartaglia, L. A., Goeddel, D. V., Reynolds, C., Figari, I. S., Weber, R. F., Fendly, B. M., et al. (1993). Stimulation of human T-cell proliferation by specific activation of the 75-kDa tumor necrosis factor receptor. Journal of Immunology, 151, 4637–4641.Google Scholar
  388. Teige, I., Liu, Y., & Issazadeh-Navikas, S. (2006). IFN-beta inhibits T cell activation capacity of central nervous system APCs. Journal of Immunology, 177, 3542–3553.Google Scholar
  389. Teige, I., Treschow, A., Teige, A., Mattsson, R., Navikas, V., Leanderson, T., et al. (2003). IFN-beta gene deletion leads to augmented and chronic demyelinating experimental autoimmune encephalomyelitis. Journal of Immunology, 170, 4776–4784.Google Scholar
  390. Tenorio, E., & Mack, D. M. (2008). Therapeutic anti-inflammatory mechanism of action of Type I interferons. Bioscience Hypotheses, 1, 218–222.CrossRefGoogle Scholar
  391. Thakker, P., Leach, M. W., Kuang, W., Benoit, S. E., Leonard, J. P., & Marusic, S. (2007). IL-23 is critical in the induction but not in the effector phase of experimental autoimmune encephalomyelitis. Journal of Immunology, 178, 2589–2598.Google Scholar
  392. ‘t Hart, B. A., Brok, H. P., Remarque, E., Benson, J., Treacy, G., Amor, S., et al. (2005). Suppression of ongoing disease in a nonhuman primate model of multiple sclerosis by a human-anti-human IL-12p40 antibody. Journal of Immunology, 175, 4761–4768.Google Scholar
  393. Theofilopoulos, A. N., Baccala, R., Beutler, B., & Kono, D. H. (2005). Type I interferons (alpha/beta) in immunity and autoimmunity. Annual Review of Immunology, 23, 307–336.PubMedCrossRefGoogle Scholar
  394. Thomas, K. E., Galligan, C. L., Newman, R. D., Fish, E. N., & Vogel, S. N. (2006). Contribution of interferon-beta to the murine macrophage response to the toll-like receptor 4 agonist, lipopolysaccharide. Journal of Biological Chemistry, 281, 31119–31130.PubMedCrossRefGoogle Scholar
  395. Toshchakov, V., Jones, B. W., Perera, P. Y., Thomas, K., Cody, M. J., Zhang, S., et al. (2002). TLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages. Nature Immunology, 3, 392–398.PubMedCrossRefGoogle Scholar
  396. Totoiu, M. O., Nistor, G. I., Lane, T. E., & Keirstead, H. S. (2004). Remyelination, axonal sparing, and locomotor recovery following transplantation of glial-committed progenitor cells into the MHV model of multiple sclerosis. Experimental Neurology, 187, 254–265.PubMedCrossRefGoogle Scholar
  397. Tran, E. H., Prince, E. N., & Owens, T. (2000). IFN-gamma shapes immune invasion of the central nervous system via regulation of chemokines. Journal of Immunology, 164, 2759–2768.Google Scholar
  398. Trapp, B. D., Peterson, J., Ransohoff, R. M., Rudick, R., Mork, S., & Bo, L. (1998). Axonal transection in the lesions of multiple sclerosis. New England Journal of Medicine, 338, 278–285.PubMedCrossRefGoogle Scholar
  399. Trapp, B. D., Ransohoff, R., & Rudick, R. (1999). Axonal pathology in multiple sclerosis: Relationship to neurologic disability. Current Opinion in Neurology, 12, 295–302.PubMedCrossRefGoogle Scholar
  400. Trebst, C., Heine, S., Lienenklaus, S., Lindner, M., Baumgartner, W., Weiss, S., et al. (2007). Lack of interferon-beta leads to accelerated remyelination in a toxic model of central nervous system demyelination. Acta Neuropathologica, 114, 587–596.PubMedCrossRefGoogle Scholar
  401. Trinchieri, G. (2003). Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nature Reviews Immunology, 3, 133–146.PubMedCrossRefGoogle Scholar
  402. Tsukada, N., Miyagi, K., Matsuda, M., Yanagisawa, N., & Yone, K. (1991). Tumor necrosis factor and interleukin-1 in the CSF and sera of patients with multiple sclerosis. Journal of the Neurological Sciences, 104, 230–234.PubMedCrossRefGoogle Scholar
  403. Ulrich, R., Seeliger, F., Kreutzer, M., Germann, P. G., & Baumgärtner, W. (2008). Limited remyelination in Theiler’s murine encephalomyelitis due to insufficient oligodendroglial differentiation of nerve/glial antigen 2 (NG2)-positive putative oligodendroglial progenitor cells. Neuropathology and Applied Neurobiology, 34, 603–620.PubMedCrossRefGoogle Scholar
  404. van Oosten, B. W., Barkhof, F., Truyen, L., Boringa, J. B., Bertelsmann, F. W., von Blomberg, B. M., et al. (1996). Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology, 47, 1531–1534.PubMedGoogle Scholar
  405. Van Ostade, X., Vandenabeele, P., Everaerdt, B., Loetscher, H., Gentz, R., Brockhaus, M., et al. (1993). Human TNF mutants with selective activity on the p55 receptor. Nature, 361, 266–269.PubMedCrossRefGoogle Scholar
  406. Vandenabeele, P., Declercq, W., Beyaert, R., & Fiers, W. (1995). Two tumour necrosis factor receptors: Structure and function. Trends in Cell Biology, 5, 392–399.PubMedCrossRefGoogle Scholar
  407. Vargas, M. E., & Barres, B. A. (2007). Why is Wallerian degeneration in the CNS so slow? Annual Review of Neuroscience, 30, 153–179.PubMedCrossRefGoogle Scholar
  408. Vela, J. M., Molina-Holgado, E., Arevalo-Martin, A., Almazan, G., & Guaza, C. (2002). Interleukin-1 regulates proliferation and differentiation of oligodendrocyte progenitor cells. Molecular and Cellular Neurosciences, 20, 489–502.PubMedCrossRefGoogle Scholar
  409. Veldhoen, M., Hocking, R. J., Flavell, R. A., & Stockinger, B. (2006). Signals mediated by transforming growth factor-beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nature Immunology, 7, 1151–1156.PubMedCrossRefGoogle Scholar
  410. Villarroya, H., Violleau, K., Ben Younes-Chennoufi, A., & Baumann, N. (1996). Myelin-induced experimental allergic encephalomyelitis in Lewis rats: Tumor necrosis factor alpha levels in serum and cerebrospinal fluid immunohistochemical expression in glial cells and macrophages of optic nerve and spinal cord. Journal of Neuroimmunology, 64, 55–61.PubMedCrossRefGoogle Scholar
  411. von Zahn, J., Moller, T., Kettenmann, H., & Nolte, C. (1997). Microglial phagocytosis is modulated by pro- and anti-inflammatory cytokines. Neuroreport, 8, 3851–3856.CrossRefGoogle Scholar
  412. Waetzig, V., Czeloth, K., Hidding, U., Mielke, K., Kanzow, M., Brecht, S., et al. (2005). c-Jun N-terminal kinases (JNKs) mediate pro-inflammatory actions of microglia. Glia, 50, 235–246.PubMedCrossRefGoogle Scholar
  413. Wahl, S. M. (1994). Transforming growth factor beta: The good, the bad, and the ugly. Journal of Experimental Medicine, 180, 1587–1590.PubMedCrossRefGoogle Scholar
  414. Wahl, S. M., Hunt, D. A., Wakefield, L. M., McCartney-Francis, N., Wahl, L. M., Roberts, A. B., et al. (1987). Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proceedings of the National Academy of Sciences of the United States of America, 84, 5788–5792.PubMedCrossRefGoogle Scholar
  415. Wajant, H., Pfizenmaier, K., & Scheurich, P. (2003). Tumor necrosis factor signaling. Cell Death and Differentiation, 10, 45–65.PubMedCrossRefGoogle Scholar
  416. Wallach, D., Varfolomeev, E. E., Malinin, N. L., Goltsev, Y. V., Kovalenko, A. V., & Boldin, M. P. (1999). Tumor necrosis factor receptor and Fas signaling mechanisms. Annual Review of Immunology, 17, 331–367.PubMedCrossRefGoogle Scholar
  417. Wang, J., Asensio, V. C., & Campbell, I. L. (2002). Cytokines and chemokines as mediators of protection and injury in the central nervous system assessed in transgenic mice. Current Topics in Microbiology and Immunology, 265, 23–48.PubMedGoogle Scholar
  418. Wang, Z., Hong, J., Sun, W., Xu, G., Li, N., Chen, X., et al. (2006). Role of IFN-gamma in induction of Foxp3 and conversion of CD4 + CD25- T cells to CD4 + Tregs. Journal of Clinical Investigation, 116, 2434–2441.PubMedGoogle Scholar
  419. Wang, Y., Lawson, M. A., Dantzer, R., & Kelley, K. W. (2010). LPS-induced indoleamine 2, 3-dioxygenase is regulated in an interferon-gamma-independent manner by a JNK signaling pathway in primary murine microglia. Brain, Behavior, and Immunity, 24, 201–209.PubMedCrossRefGoogle Scholar
  420. Wei, R., & Jonakait, G. M. (1999). Neurotrophins and the anti-inflammatory agents interleukin-4 (IL-4), IL-10, IL-11 and transforming growth factor-beta1 (TGF-beta1) down-regulate T cell costimulatory molecules B7 and CD40 on cultured rat microglia. Journal of Neuroimmunology, 95, 8–18.PubMedCrossRefGoogle Scholar
  421. Weinger, J. G., Omari, K. M., Marsden, K., Raine, C. S., & Shafit-Zagardo, B. (2009). Up-regulation of soluble Axl and Mer receptor tyrosine kinases negatively correlates with Gas6 in established multiple sclerosis lesions. American Journal of Pathology, 175, 283–293.PubMedCrossRefGoogle Scholar
  422. Weinstock-Guttman, B., Ramanathan, M., & Zivadinov, R. (2008). Interferon-beta treatment for relapsing multiple sclerosis. Expert Opinion on Biological Therapy, 8, 1435–1447.PubMedCrossRefGoogle Scholar
  423. Wesche, H., Henzel, W. J., Shillinglaw, W., Li, S., & Cao, Z. (1997). MyD88: An adapter that recruits IRAK to the IL-1 receptor complex. Immunity, 7, 837–847.PubMedCrossRefGoogle Scholar
  424. Wesemann, D. R., Dong, Y., O’Keefe, G. M., Nguyen, V. T., & Benveniste, E. N. (2002). Suppressor of cytokine signaling 1 inhibits cytokine induction of CD40 expression in macrophages. Journal of Immunology, 169, 2354–2360.Google Scholar
  425. Williams, K., Dooley, N., Ulvestad, E., Becher, B., & Antel, J. P. (1996). IL-10 production by adult human derived microglial cells. Neurochemistry International, 29, 55–64.PubMedCrossRefGoogle Scholar
  426. Windhagen, A., Newcombe, J., Dangond, F., Strand, C., Woodroofe, M. N., Cuzner, M. L., et al. (1995). Expression of costimulatory molecules B7-1 (CD80), B7-2 (CD86), and interleukin 12 cytokine in multiple sclerosis lesions. Journal of Experimental Medicine, 182, 1985–1996.PubMedCrossRefGoogle Scholar
  427. Wirjatijasa, F., Dehghani, F., Blaheta, R. A., Korf, H. W., & Hailer, N. P. (2002). Interleukin-4, interleukin-10, and interleukin-1-receptor antagonist but not transforming growth factor-beta induce ramification and reduce adhesion molecule expression of rat microglial cells. Journal of Neuroscience Research, 68, 579–587.PubMedCrossRefGoogle Scholar
  428. Wolf, S. F., Temple, P. A., Kobayashi, M., Young, D., Dicig, M., Lowe, L., et al. (1991). Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. Journal of Immunology, 146, 3074–3081.Google Scholar
  429. Wolswijk, G. (2002). Oligodendrocyte precursor cells in the demyelinated multiple sclerosis spinal cord. Brain, 125, 338–349.PubMedCrossRefGoogle Scholar
  430. Xiao, B. G., Bai, X. F., Zhang, G. X., Hojeberg, B., & Link, H. (1996). Shift from anti- to proinflammatory cytokine profiles in microglia through LPS- or IFN-gamma-mediated pathways. Neuroreport, 7, 1893–1898.PubMedCrossRefGoogle Scholar
  431. Xiao, B. G., Ma, C. G., Xu, L. Y., Link, H., & Lu, C. Z. (2008). IL-12/IFN-gamma/NO axis plays critical role in development of Th1-mediated experimental autoimmune encephalomyelitis. Molecular Immunology, 45, 1191–1196.PubMedCrossRefGoogle Scholar
  432. Yadav, M. C., Burudi, E. M., Alirezaei, M., Flynn, C. C., Watry, D. D., Lanigan, C. M., et al. (2007). IFN-gamma-induced IDO and WRS expression in microglia is differentially regulated by IL-4. Glia, 55, 1385–1396.PubMedCrossRefGoogle Scholar
  433. Yaguchi, M., Ohta, S., Toyama, Y., Kawakami, Y., & Toda, M. (2008). Functional recovery after spinal cord injury in mice through activation of microglia and dendritic cells after IL-12 administration. Journal of Neuroscience Research, 86, 1972–1980.PubMedCrossRefGoogle Scholar
  434. Yamamoto, M., Sato, S., Hemmi, H., Hoshino, K., Kaisho, T., Sanjo, H., et al. (2003a). Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science, 301, 640–643.PubMedCrossRefGoogle Scholar
  435. Yamamoto, M., Sato, S., Hemmi, H., Uematsu, S., Hoshino, K., Kaisho, T., et al. (2003b). TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nature Immunology, 4, 1144–1150.PubMedCrossRefGoogle Scholar
  436. Yan, H., & Rivkees, S. (2002). Hepatocyte growth factor stimulates the proliferation and migration of oligodendrocyte precursor cells. Journal of Neuroscience Research, 69, 597–606.PubMedCrossRefGoogle Scholar
  437. Yoshimura, A. (2005). Negative regulation of cytokine signaling. Clinical Reviews in Allergy and Immunology, 28, 205–220.PubMedCrossRefGoogle Scholar
  438. Young, D. A., Lowe, L. D., Booth, S. S., Whitters, M. J., Nicholson, L., Kuchroo, V. K., et al. (2000). IL-4, IL-10, IL-13, and TGF-beta from an altered peptide ligand-specific Th2 cell clone down-regulate adoptive transfer of experimental autoimmune encephalomyelitis. Journal of Immunology, 164, 3563–3572.Google Scholar
  439. Yu, M., Nishiyama, A., Trapp, B. D., & Tuohy, V. K. (1996). Interferon-beta inhibits progression of relapsing-remitting experimental autoimmune encephalomyelitis. Journal of Neuroimmunology, 64, 91–100.PubMedCrossRefGoogle Scholar
  440. Zhang, B., Harness, J., Somodevilla-Torres, M. J., Hillyard, N. C., Mould, A. W., Alewood, D., et al. (2000). Early pregnancy factor suppresses experimental autoimmune encephalomyelitis induced in Lewis rats with myelin basic protein and in SJL/J mice with myelin proteolipid protein peptide 139–151. Journal of the Neurological Sciences, 182, 5–15.PubMedCrossRefGoogle Scholar
  441. Zhao, C., Fancy, S. P., ffrench-Constant, C., & Franklin, R. J. (2008). Osteopontin is extensively expressed by macrophages following CNS demyelination but has a redundant role in remyelination. Neurobiology of Diseases, 31, 209–217.CrossRefGoogle Scholar
  442. Zhao, W., Xie, W., Xiao, Q., Beers, D. R., & Appel, S. H. (2006). Protective effects of an anti-inflammatory cytokine, interleukin-4, on motoneuron toxicity induced by activated microglia. Journal of Neurochemistry, 99, 1176–1187.PubMedCrossRefGoogle Scholar
  443. Zheng, L., Fisher, G., Miller, R. E., Peschon, J., Lynch, D. H., & Lenardo, M. J. (1995). Induction of apoptosis in mature T cells by tumour necrosis factor. Nature, 377, 348–351.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Tobias D. Merson
    • 1
  • Michele D. Binder
    • 1
  • Trevor J. Kilpatrick
    • 1
  1. 1.Florey Neuroscience Institutes and the Centre for NeuroscienceUniversity of MelbourneParkvilleAustralia

Personalised recommendations