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Glutamate uptake by astrocytes has been postulated to play a neuroprotective role during brain inflammation. Using primary human fetal astrocyte cultures, we investigated the influence of selected cytokines on glutamate uptake activity. Interleukin (IL)-1beta and tumor necrosis factor-alpha dose-dependently inhibited astrocyte glutamate uptake, whereas interferon (IFN)-gamma alone stimulated this activity. The nitric oxide synthase inhibitor, N(G)-monomethyl-L-arginine, blocked IL-1beta-mediated inhibition of glutamate uptake, suggesting involvement of nitric oxide in the effect of IL-1beta. IL-1 receptor antagonist protein totally reversed the inhibitory effect of cytokines, suggesting a critical role of IL-1beta. The anti-inflammatory cytokine IFN-beta blocked cytokine (IL-1beta plus IFN-gamma)-induced inhibition of glutamate uptake with a corresponding reduction in nitric oxide generation. Taken together, these findings suggest that proinflammatory cytokines inhibit astrocyte glutamate uptake by a mechanism involving nitric oxide, and that IFN-beta may exert a therapeutically beneficial effect by blocking cytokine-induced nitric oxide production in inflammatory diseases of the brain., (Copyright 2000 S. Karger AG, Basel)

Apoptosis of brain cells is observed in many inflammatory disorders of the central nervous system. Nitric oxide (NO) has been shown to induce apoptosis in several brain cell types, but not previously in astrocytes. In the present study, the hypothesis was examined that interleukin (IL)-1beta would induce production of NO by astrocytes which, in turn, would signal apoptotic death in these glial cells. TUNEL staining demonstrated apoptosis in astrocytes treated with IL-1beta. Using an ELISA method, IL-1 receptor antagonist protein completely abrogated this astrocyte apoptosis, while N(G)monomethyl-L-arginine partially prevented apoptosis but almost entirely blocked NO production. Thus, IL-1beta appears to signal apoptosis of astrocytes by a mechanism involving, in part, the induction of NO.