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 excitotoxicity by taking up excess glutamate and converting it to glutamine via the enzyme glutamine synthetase. In a number of cell types, glucocorticoid hormones induce glutamine synthetase. Glucocorticoids also down-regulate many genes induced by proinflammatory cytokines. As the glucocorticoid receptor has been shown to interact with transcription factors that may also be activated by the proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), we hypothesized that IL-1beta or TNF-alpha might oppose the induction of glutamine synthetase by dexamethasone. Primary mouse cortical astrocytes were treated with 10(-7) M dexamethasone and doses of IL-1beta or TNF-alpha ranging from 0.02 to 5 ng/ml or 0.05 to 20 ng/ml, respectively. We found that both cytokines attenuated the dexamethasone induction of glutamine synthetase protein at 24 h and that the effect was dose-dependent. We also found that IL-1beta and TNF-alpha inhibited the induction of glutamine synthetase mRNA by dexamethasone, and that the induction of enzymatic activity was similarly prevented by IL-1beta. As glutamine synthetase can be induced by physiological levels of glucocorticoids, the release of proinflammatory cytokines following acute injury or in neurodegenerative disorders may hinder the ability of astrocytes to protect neurons from excitotoxicity.
Huang
T L
TL
Interdepartmental Graduate Program in Neuroscience, University of Rochester School of Medicine and Dentistry, New York, USA.
O'Banion
M K
MK
D000818:Animals; D001253:Astrocytes / Q000201:enzymology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003907:Dexamethasone / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics; D005974:Glutamate-Ammonia Ligase / Q000096:biosynthesis* / Q000235:genetics; D007375:Interleukin-1 / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007375:Interleukin-1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D005974:Glutamate-Ammonia Ligase