Effects of transforming growth factor-β on murine astrocyte glutamine synthetase activity: Implications in neuronal injury

Chun C. Chao, Shuxian Hu, Monica Tsang, James Weatherbee, Thomas W Molitor, W. Robert Andersen, Phillip K. Peterson

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64 Scopus citations

Abstract

Cytokines have been implicated in the pathogenesis of a number of brain diseases in which neurological dysfunction has been attributed to a change in amino acid neurotransmitter metabolism. In the present in vitro study, we investigated the effects of cytokines on astrocyte glutamine synthetase (GS) activity and subsequently on N-methyl-D-asparate (NMDA) receptor-mediated neurotoxicity. Proinflammatory cytokines IL-1α, IL-1β, and IL-6 at a concentration of 20 ng/ml did not affect GS activity; however, tumor necrosis factor-α inhibited this activity by 20% in mixed neuronal/astrocyte cultures. Treatment for 24 h with transforming growth factor (TGF)-β1 or -β2 inhibited up to 60% GS activity. TGF-β2 also inhibited GS in enriched astrocyte cultures with an ED50 of 10 pg/ml. Antibodies specific to TGF-β2 blocked this effect. Treatment of astrocytes with TGF-β2 (250 pg/ml) resulted in markedly dilated rough endoplasmic reticulum. Since astrocyte GS may play a protective role in NMDA receptor-mediated neurotoxicity, we treated mixed neuronal / astrocyte cultures with TGF-β2 (250 pg/ml) and found a threefold potentiation of NMDA receptor-mediated neurotoxicity. These data suggest that TGF-β impairs astrocyte GS function and enhances neurotoxicity, thus providing insight into understanding one mechanism of cytokine-mediated central nervous system disease.

Original languageEnglish (US)
Pages (from-to)1786-1793
Number of pages8
JournalJournal of Clinical Investigation
Volume90
Issue number5
DOIs
StatePublished - Nov 1992

Keywords

  • Cytokines
  • Excitotoxicity
  • N-methyl-D-asparate receptors
  • Tumor necrosis factor-α

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