INTERLEUKIN-1-BETA AND TUMOR-NECROSIS-FACTOR-ALPHA SUPPRESS DEXAMETHASONE INDUCTION OF GLUTAMINE-SYNTHETASE IN PRIMARY MOUSE ASTROCYTES

Astrocytes play a key role in the protection of neurons from excitotox icity by taking up excess glutamate and converting it to glutamine via the enzyme glutamine synthetase, In a number of cell types, glucocort icoid hormones induce glutamine synthetase. Glucocorticoids also down- regulate many genes induced by proinflammatory cytokines, As the gluco corticoid receptor has been shown to interact with transcription facto rs that may also be activated by the proinflammatory cytokines interle ukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha), w e hypothesized that IL-1 beta or TNF-alpha might oppose the induction of glutamine synthetase by dexamethasone. Primary mouse cortical astro cytes were treated with 10(-7) M dexamethasone and doses of IL-1 beta or TNF-alpha ranging from 0.02 to 5 ng/ml or 0.05 to 20 ng/ml, respect ively. We found that both cytokines attenuated the dexamethasone induc tion of glutamine synthetase protein at 24 h and that the effect was d ose-dependent. We also found that IL-1 beta and TNF-alpha inhibited th e induction of glutamine synthetase mRNA by dexamethasone, and that th e induction of enzymatic activity was similarly prevented by IL-1 beta . As glutamine synthetase can be induced by physiological levels of gl ucocorticoids, the release of proinflammatory cytokines following acut e injury or in neurodegenerative disorders may hinder the ability of a strocytes to protect neurons from excitotoxicity.