Effect of cytokines on growth of Toxoplasma gondii in murine astrocytes.
Cytokines play a significant role in the regulation of Toxoplasma gondii in the central nervous system. Cytokine-activated microglia are important host defense cells in central nervous system infections. Recent evidence indicates that astrocytes can also be activated by cytokines to inhibit intracellular pathogens. In this study, we examined the effect of gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1 on the growth of T. gondii in a primary murine astrocyte culture. Pretreatment of astrocytes with IFN-gamma resulted in 65% inhibition of T. gondii growth. Neither TNF-alpha, IL-1, nor IL-6 alone had any effect on T. gondii growth. IFN-gamma in combination with either TNF-alpha, IL-1, or IL-6 caused a 75 to 80% inhibition of growth. While nitric oxide was produced by astrocytes treated with these cytokines, inhibition of T. gondii growth was not reversed by the addition of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine. Furthermore, IFN-gamma in combination with IL-1, IL-6, or TNF-alpha also induced inhibition in astrocytes derived from syngeneic mice deficient in the enzyme inducible nitric oxide synthase. This finding suggests that the mechanism of cytokine inhibition is not nitric oxide mediated. Similarly, the addition of tryptophan had no effect on inhibition, indicating that the mechanism was not mediated via induction of the enzyme indoleamine 2, 3-dioxygenase. The mechanism of inhibition remains to be elucidated. Results from this study demonstrate that cytokine-activated astrocytes are capable of significantly inhibiting the growth of T. gondii. These data indicate that astrocytes may be important host defense cells in controlling toxoplasmosis in the brain.
Halonen
S K
SK
Departments of Neurology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Chiu
F
F
Weiss
L M
LM
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000469:parasitology*; D002455:Cell Division; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004347:Drug Interactions; D007371:Interferon-gamma / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000172:deficiency; D052247:Nitric Oxide Synthase Type II; D014122:Toxoplasma / Q000187:drug effects*; D016781:Toxoplasmosis, Cerebral / Q000276:immunology; D014364:Tryptophan / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D016207:Cytokines; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D014364:Tryptophan; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse