CYTOKINE RESPONSES INDUCED BY TOXOPLASMA-GONDII IN ASTROCYTES AND MICROGLIAL CELLS

To investigate the role of astroglia in intracerebral immune response to Toxoplasma gondii, astrocytes cultured from mouse brain were inocul ated with mouse-virulent or -avirulent toxoplasma strains. In comparis on to microglia/brain macrophages, astrocytes as host cells allowed st ronger proliferation of avirulent parasites. Toxoplasma infection of a stroglia was accompanied by release of interleukin- (IL)1 alpha, IL-6, and granulocyte/macrophage colony-stimulating factor (GM-CSF) activit y, whereas alternative challenge by lipopolysaccharide (LPS) evoked no IL-1 response and significantly higher titers of IL-6 and GMCSF At th e mRNA level, both stimuli induced transcription of all three cytokine s in astrocytes. Secretion of IL-1 and IL-6 upon infection was trigger ed by T. gondii brady- and tachyzoites in a time- and dose-dependent m anner. Heat killing of parasites, but not an exposure to polymyxin B, abrogated their cytokine-inducing activity, thus indicating that an LP S-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 LP S-triggered, IL-6 response of astrocytes resisted to antagonization wi th IL-10. The IL-6 response of parasitized astroglia was upregulated b y external tumor necrosis factor (TNF)-alpha and transforming growth f actor (TGF)-beta(1), with only TNF-alpha enhancing simultaneous releas e of IL-1. Substantial secretion of IL-10 and TNF-alpha was detected i n T. gondii-infected microglia, but not in astrocyte cultures. A possi bly 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-indu ced pathway of astroglia activation characterized by the release of IL -1 which may drive local inflammatory reaction both at initial infecti on of the brain and during reactivating toxoplasmosis.