Cytokines may play a pathogenetic role in the brain. Using human fetal brain cell cultures, we investigated whether cytokines released during inflammation modulate neuronal injury. Exposure of human fetal neuronal cells to the excitatory amino acid neurotransmitter, glutamate, for 6 days resulted in a dose-dependent cell loss. Tumor necrosis factor (TNF)-alpha potentiated glutamate neurotoxicity. This TNF alpha-potentiated glutamate neurotoxicity was blocked by the glutamate receptor antagonists, 2-APV and MK-801, suggesting that the potentiating effect of TNF alpha is predominantly mediated by a glutamate receptor mechanism. Exposure of neuronal cultures to TNF alpha for 5 days resulted in a 27% decrease in astrocyte glutamine synthetase and in a 50% inhibition of 3H-glutamate uptake, suggesting that the effect of TNF alpha indirectly involves glutamate metabolism. These findings suggest that under pathologic conditions, TNF alpha may impair embryonic development of the brain by exacerbating excitotoxicity.