title: IL-1β and TNF-α induce neurotoxicity through glutamate production: a potential role for neuronal glutaminase.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Ye
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Huang
authors.forename: Lixia
authors.initials: L
authors.lastname: Zhao
authors.forename: Yuju
authors.initials: Y
authors.lastname: Li
authors.forename: Lijun
authors.initials: L
authors.lastname: Sun
authors.forename: You
authors.initials: Y
authors.lastname: Zhou
authors.forename: Guanxiang
authors.initials: G
authors.lastname: Qian
authors.forename: Jialin C
authors.initials: JC
authors.lastname: Zheng
mesh_terms: D000818:Animals; D016923:Cell Death; D002540:Cerebral Cortex / Q000166:cytology; D003600:Cytosol / Q000201:enzymology; D018792:Encephalitis, Viral / Q000201:enzymology / Q000821:virology; D005110:Extracellular Space / Q000378:metabolism; D018698:Glutamic Acid / Q000096:biosynthesis*; D005972:Glutaminase / Q000378:metabolism*; D015497:HIV-1; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism* / Q000633:toxicity; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000201:enzymology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000633:toxicity; D015854:Up-Regulation
chemical_list: D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D018698:Glutamic Acid; D005972:Glutaminase