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2292566 
Journal Article 
IL-1 and TNF- induce neurotoxicity through glutamate production: a potential role for neuronal glutaminase 
Ye, L; Huang, Y; Zhao, L; Li, Y; Sun, L; Zhou, You; Qian, G; Zheng, JC 
2013 
Yes 
Journal of Neurochemistry
ISSN: 0022-3042
EISSN: 1471-4159 
125 
6 
897-908 
23578284 
WOS:000320041700010 
Glutaminase 1 is the main enzyme responsible for glutamate production in mammalian cells. The roles of macrophage and microglia glutaminases in brain injury, infection, and inflammation are well documented. However, little is known about the regulation of neuronal glutaminase, despite neurons being a predominant cell type of glutaminase expression. Using primary rat and human neuronal cultures, we confirmed that interleukin-1 (IL-1) and tumor necrosis factor- (TNF-), two pro-inflammatory cytokines that are typically elevated in neurodegenerative disease states, induced neuronal death and apoptosis in vitro. Furthermore, both intracellular and extracellular glutamate levels were significantly elevated following IL-1 and/or TNF- treatment. Pre-treatment with N-Methyl-d-aspartate (NMDA) receptor antagonist MK-801 blocked cytokine-induced glutamate production and alleviated the neurotoxicity, indicating that IL-1 and/or TNF- induce neurotoxicity through glutamate. To determine the potential source of excess glutamate production in the culture during inflammation, we investigated the neuronal glutaminase and found that treatment with IL-1 or TNF- significantly upregulated the kidney-type glutaminase (KGA), a glutaminase 1 isoform, in primary human neurons. The up-regulation of neuronal glutaminase was also demonstrated in situ in a murine model of HIV-1 encephalitis. In addition, IL-1 or TNF- treatment increased the levels of KGA in cytosol and TNF- specifically increased KGA levels in the extracellular fluid, away from its main residence in mitochondria. Together, these findings support neuronal glutaminase as a potential component of neurotoxicity during inflammation and that modulation of glutaminase may provide therapeutic avenues for neurodegenerative diseases. 
glutamate; glutaminase; inflammation; neurotoxicity