Human MBP-specific T cells regulate IL-6 gene expression in astrocytes through cell-cell contacts and soluble factors

Glia. 2001 Sep;35(3):224-33. doi: 10.1002/glia.1087.

Abstract

One of the distinctive features of multiple sclerosis (MS) attacks is homing to the CNS of activated T cells able to orchestrate humoral and cell-based events, resulting in immune-mediated injury to myelin and oligodendrocytes. Of the complex interplay occurring between T cells and CNS constituents, we have examined some aspects of T-cell interactions with astrocytes, the major components of the glial cells. Specifically, we focused on the ability of T cells to regulate the gene expression of interleukin-6 (IL-6) in astrocytes, based on previous evidence showing the involvement of this cytokine in CNS disorders. We found that T-cell adhesion and T-cell soluble factors induce IL-6 gene expression in U251 astrocytes through distinct signaling pathways, respectively, resulting in the activation of NF-kappaB and IRF-1 transcription factors. In a search for effector molecules at the astrocyte surface, we found that alpha3beta1 integrins play a role in NF-kappaB activation induced by T-cell contact, whereas interferon-gamma (IFN-gamma) receptors dominate in IRF-1 induction brought about by T-cell-derived soluble factors. Similar phenomena were observed also in normal fetal astrocyte cultures. We therefore propose that through astrocyte induction, T cells may indirectly regulate the availability of a cytokine which is crucial in modulating fate and behavior of cell populations involved in the pathogenesis of MS inflammatory lesions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Astrocytes / immunology*
  • Astrocytes / metabolism
  • Binding Sites / drug effects
  • Binding Sites / physiology
  • Cell Adhesion / immunology
  • Cell Communication / immunology*
  • Cells, Cultured / drug effects
  • Cells, Cultured / immunology
  • Cells, Cultured / metabolism
  • Cloning, Molecular
  • DNA-Binding Proteins / drug effects
  • DNA-Binding Proteins / immunology
  • DNA-Binding Proteins / metabolism
  • Fetus
  • Gene Expression Regulation / immunology*
  • Humans
  • Integrin beta1 / drug effects
  • Integrin beta1 / immunology
  • Integrin beta1 / metabolism
  • Interferon Regulatory Factor-1
  • Interferon-gamma / pharmacology
  • Interleukin-6 / genetics*
  • Interleukin-6 / metabolism
  • Multiple Sclerosis / genetics
  • Multiple Sclerosis / immunology*
  • Multiple Sclerosis / physiopathology
  • Myelin Basic Protein / immunology*
  • NF-kappa B / metabolism
  • Phenotype
  • Phosphoproteins / drug effects
  • Phosphoproteins / immunology
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • STAT1 Transcription Factor
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Trans-Activators / drug effects
  • Trans-Activators / metabolism
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / immunology
  • Up-Regulation / drug effects
  • Up-Regulation / immunology

Substances

  • DNA-Binding Proteins
  • IRF1 protein, human
  • Integrin beta1
  • Interferon Regulatory Factor-1
  • Interleukin-6
  • Myelin Basic Protein
  • NF-kappa B
  • Phosphoproteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Trans-Activators
  • Interferon-gamma

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