Cytokine responses induced by Toxoplasma gondii in astrocytes and microglial cells

Eur J Immunol. 1997 Jun;27(6):1539-48. doi: 10.1002/eji.1830270633.

Abstract

To investigate the role of astroglia in intracerebral immune response to Toxoplasma gondii, astrocytes cultured from mouse brain were inoculated with mouse-virulent or -avirulent toxoplasma strains. In comparison to microglia/ brain macrophages, astrocytes as host cells allowed stronger proliferation of avirulent parasites. Toxoplasma infection of astroglia was accompanied by release of interleukin- (IL)1 alpha, IL-6, and granulocyte/macrophage colony-stimulating factor (GM-CSF) activity, whereas alternative challenge by lipopolysaccharide (LPS) evoked no IL-1 response and significantly higher titers of IL-6 and GM-CSF. At the mRNA level, both stimuli induced transcription of all three cytokines in astrocytes. Secretion of IL-1 and IL-6 upon infection was triggered by T. gondii brady- and tachyzoites in a time- and dose-dependent manner. Heat killing of parasites, but not an exposure to polymyxin B, abrogated their cytokine-inducing activity, thus indicating that an LPS-independent stimulus is provided by T. gondii. When administered in combination, LPS synergistically augmented the IL-1-inducing effect of toxoplasma infection. In comparison, T. gondii-induced, but not an LPS-triggered, IL-6 response of astrocytes resisted to antagonization with IL-10. The IL-6 response of parasitized astroglia was up-regulated by external tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta 1, with only TNF-alpha enhancing simultaneous release of IL-1. Substantial secretion of IL-10 and TNF-alpha was detected in T. gondii-infected microglia, but not in astrocyte cultures. A possibly autocrine stimulation of infected astroglia via IL-1 was found to be unlikely, since addition of IL-1 receptor antagonist did not affect the release of IL-6 and GM-CSF while inhibiting these responses in IL-1-treated cells. The findings substantiate a separate, T. gondii-induced pathway of astroglia activation characterized by the release of IL-1 which may drive local inflammatory reaction both at initial infection of the brain and during reactivating toxoplasmosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / immunology*
  • Astrocytes / metabolism
  • Astrocytes / parasitology
  • Cytokines / biosynthesis*
  • Cytokines / metabolism
  • Down-Regulation / drug effects
  • Down-Regulation / immunology
  • Female
  • Gene Expression Regulation
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Interleukin-1 / genetics
  • Interleukin-10 / genetics
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Lipopolysaccharides / pharmacology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Microglia / immunology*
  • Microglia / metabolism
  • Microglia / parasitology
  • Toxoplasma / growth & development
  • Toxoplasma / pathogenicity
  • Toxoplasma / physiology*
  • Toxoplasmosis, Animal / immunology
  • Toxoplasmosis, Animal / parasitology
  • Transcription, Genetic
  • Transforming Growth Factor beta / physiology
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / physiology
  • Up-Regulation / drug effects
  • Up-Regulation / immunology
  • Virulence

Substances

  • Cytokines
  • Interleukin-1
  • Interleukin-6
  • Lipopolysaccharides
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Granulocyte-Macrophage Colony-Stimulating Factor