Astrocytes play an important role in nervous system homeostasis. In particular, 
they contribute to the regulation of local energy metabolism and to oxidative 
stress defence. In previous experiments, we showed that long-term treatment with 
interleukin 1alpha (IL-1alpha) or tumor necrosis factor-alpha (TNFalpha) alone 
increases glucose utilization in primary culture of mouse astrocytes. In our 
study, we report that a combination of IL-1beta and TNFalpha exerts a 
synergistic effect on glucose utilization and markedly modifies the metabolic 
phenotype of astrocytes. Thus, IL-1beta+TNFalpha treated astrocytes show a 
marked decrease in glycogen levels, a slight but not significant decrease in 
lactate release as well as a massive increase in both the pentose phosphate 
pathway and TCA cycle activities. Glutamate-stimulated glucose utilization and 
lactate release, a typical feature of astrocyte energy metabolism, are altered 
after pretreatment with IL-1beta+TNFalpha. As far as mechanisms for oxidative 
stress defence are concerned, we observed that treatment with IL-1beta+TNFalpha 
decreases cellular glutathione content and increases glutathione release into 
the extracellular space while stimulating superoxide anion and nitric oxide 
production as well as H(2)O(2) release. Interestingly, stimulation of glucose 
utilization by IL-1beta+TNFalpha is not affected by the antioxidant 
N-acetyl-L-cysteine, suggesting that cellular stress does not account for this 
effect. Finally, the effects of cytokines on glucose utilization appear to 
involve multiple signaling cascades including the phosphoinositide 3-kinase and 
mitogen-activated protein kinases. Taken together these results establish that a 
proinflammatory environment such as observed in several neuropathological 
conditions including Alzheimer's disease, markedly modifies the metabolic 
phenotype of astrocytes.