Research paper
Cytokines in relapsing experimental autoimmune encephalomyelitis in DA rats: persistent mRNA expression of proinflammatory cytokines and absent expression of interleukin-10 and transforming growth factor-β

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Abstract

Experimental autoimmune encephalomyelitis (EAE) in rats is typically a brief and monophasic disease with sparse demyelination. However, inbred DA rats develop a demyelinating, prolonged and relapsing encephalomyelitis after immunization with rat spinal cord in incomplete Freund's adjuvant. This model enables studies of mechanisms related to chronicity and demyelination, two hallmarks of multiple sclerosis (MS). Here we have investigated, in situ, the dynamics of cytokine mRNA expression in the central nervous system (CNS) and peripheral lymphoid organs (lymph node cells and splenocytes) of diseased DA rats. We demonstrate that peripheral lymphoid cells stimulated in vitro with encephalitogenic peptides 69–87 and 87–101 of myelin basic protein responded with high mRNA expression for proinflammatory cytokines; Interferon-7, interleukin-12 (IL-12), tumour necrosis factors α and β, IL-1β and cytolysin. A high expression of mRNA for these proinflammatory cytokines was also observed in the CNS where it was accompanied by classical signs of inflammation such as expression of major histocompatibility complex class I and II, CD4, CDS and IL-2 receptor. The expression of mRNA for proinflammatory cytokines was remarkably long-lasting in DA rats as compared to LEW rats which display a brief and monophasic EAE. Furthermore, mRNAs for putative immunodownmodulatory cytokines i.e. transforming growth factor-β (TGF-/3), IL-10 and IL-4 were almost absent in DA rats, in both the CNS and in vitro stimulated peripheral lymphoid cells, while their levels were elevated in the CNS of LEW rats during the recovery phase. We conclude that the MS-like prolonged and relapsing EAE in DA rats is associated with a prolonged production of proinflammatory cytokines and/or low or absent production of immunodownmodulatory cytokines.

References (50)

  • S.H. Chan et al.

    Induction of Interferon-γ production by natural killer cell stimulatory factor: Characterization of the responder cells and synergy with other inducers

    J. Exp. Med.

    (1991)
  • M.A. Collait et al.

    Gamma-interferon enhances macrophage transcription of the tumour necrosis factor/cachectin, interleukin-1 and urokinase genes, which are controlled by short-lived repressors

    J. Exp. Med.

    (1986)
  • C-H.J. Chou et al.

    The major site of guinea pig myelin basic protein encephalitogenic in Lewis rats

    J. Neurochem

    (1977)
  • R. de Waal-Malefyt et al.

    IL-10 inhibits cytokine synthesis by human monocytes: An autoregulatory role of IL-10 produced by monocytes

    J. Exp. Med.

    (1991)
  • A.M. Duijvestijn et al.

    Interferon-γ regulates an antigen specific for endothelial cells involved in lymphocyte traffic

  • T.T. Doung et al.

    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

    J. Neuroimmunol.

    (1992)
  • D.F. Fiorentino et al.

    IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells

    J. Immunol.

    (1991)
  • D.L. Gasser et al.

    Genetic control of resistance to clinical EAE accompanied by histological symptoms

    Immunogenetics

    (1990)
  • H. Heremans et al.

    Protective effects of anti-interleukin-6 antibody against endotoxin, associated with paradoxically increased IL-6 levels

    Eur. J. Immunol.

    (1992)
  • C.S. Hsieh et al.

    Development of TH1 CD4+ T cells through IL-12 produced by Listeria-indaced macrophages

    Science

    (1993)
  • S. Issazadeh et al.

    Interferon-γ, interleukin-4 and transforming growth factor-β in experimental allergic encephalomyelitis in Lewis rats: Dynamics of cellular mRNA expression in the central nervous system and lymphoid cells

    J. Neurosci. Res.

    (1995)
  • L. Jansson et al.

    Spreading of the immune response to different myelin basic protein peptides in chronic experimental autoimmune encephalomyelitis in B10.RIII mice

    Eur. J. Immunol.

    (1995)
  • L.D. John et al.

    Experimental allergic encephalomyelitis: Neutralizing antibody to TGF-β enhances clinical severity of the disease

    J. Neuroimmunol.

    (1993)
  • R. Kamijo et al.

    Mice that lack the interferon-gamma receptor have profoundly altered responses to infection with Bacillius Calmette-Guerin and subsequent challenge with lipopolysaccharides

    J. Exp. Med.

    (1993)
  • M.K. Kennedy et al.

    Interleukin-12 regulates the proliferation of Thl, but not Th2 or Th0, clones

    Eur. J. Immunol.

    (1994)
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