Effects of Transforming Growth Factor - , 8 on Murine Astrocyte Glutamine Synthetase Activity

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 ofcytokines on astrocyte glutamine synthetase (GS) activity and subsequently on N-methyl-D-asparate (NMDA) receptor-mediated neurotoxicity. Proinflammatory cytokines IL-la, IL-1,6, and IL-6 at a concentration of 20 ng/ml did not affect GS activity; however, tumor necrosis factor-a inhibited this activity by 20% in mixed neuronal/astrocyte cultures. Treatment for 24 h with transforming growth factor (TGF)-f91 or -,62 inhibited up to 60% GS activity. TGF-#2 also inhibited GS in enriched astrocyte cultures with an ED5o of 10 pg/ml. Antibodies specific to TGF-,62 blocked this effect. Treatment of astrocytes with TGF-jf2 (250 pg/ml) resulted in markedly dilated rough endoplasmic reticulum. Since astrocyte GS may play a protective role inNMDA receptor-mediated neurotoxicity, we treated mixed neuronal/ astrocyte cultures with TGF-,2 (250 pg/ml) and found a threefold potentiation ofNMDA receptor-mediated neurotoxicity. These data suggest that TGF-,8 impairs astrocyte GS function and enhances neurotoxicity, thus providing insight into understanding one mechanism of cytokine-mediated central nervous system disease. (J. Clin. Invest. 1992. 90:1786-1793.)