IL-1β and TNF-α induce neurotoxicity through glutamate production: a potential role for neuronal glutaminase
Article first published online: 3 MAY 2013
© 2013 International Society for Neurochemistry
Journal of Neurochemistry
Volume 125, Issue 6, pages 897–908, June 2013
How to Cite
J. Neurochem.(2013) 125, 897–908.
- Issue published online: 5 JUN 2013
- Article first published online: 3 MAY 2013
- Accepted manuscript online: 11 APR 2013 11:20AM EST
- Manuscript Accepted: 9 APR 2013
- Manuscript Revised: 6 FEB 2013
- Manuscript Received: 2 NOV 2012
- National Institutes of Health. Grant Numbers: R01 NS 41858-01, R01 NS 061642-01, 3R01NS61642-2S1, R21 MH 083525-01, P01 NS043985, P20 RR15635-01
- National Natural Science Foundation of China (NSFC). Grant Number: # 81028007
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-1β (IL-1β) and tumor necrosis factor-α (TNF-α), 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-1β and/or TNF-α 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-1β and/or TNF-α 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-1β or TNF-α 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-1β or TNF-α treatment increased the levels of KGA in cytosol and TNF-α 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.