title: Interleukin-1β protects astrocytes against oxidant-induced injury via an NF-κB-dependent upregulation of glutathione synthesis.
abstract: Astrocytes produce and export the antioxidant glutathione (GSH). Previously, we found that interleukin-1β (IL-1β) enhanced the expression of astrocyte system xc (-) , the transporter that delivers the rate-limiting substrate for GSH synthesis-cyst(e)ine. Herein, we demonstrate directly that IL-1β mediates a time-dependent increase in extracellular GSH levels in cortical astrocyte cultures, suggesting both enhanced synthesis and export. This increased GSH production was blocked by inhibition of nuclear factor-κB (NF-κB) activity but not by inhibition of p38 MAPK. To determine whether this increase could provide protection against oxidative stress, the oxidants tert-butyl hydroperoxide (tBOOH) and ferrous sulfate (FeSO4 ) were employed. IL-1β treatment prevented the increase in reactive oxygen species produced in astrocytes following tBOOH exposure. Additionally, the toxicity induced by tBOOH or FeSO4 exposure was significantly attenuated following treatment with IL-1β, an effect reversed by concomitant exposure to l-buthionine-S,R-sulfoximine (BSO), which prevented the IL-1β-mediated rise in GSH production. IL-1β failed to increase GSH or to provide protection against t-BOOH toxicity in astrocyte cultures derived from IL-1R1 null mutant mice. Overall, our data indicate that under certain conditions IL-1β may be an important stimulus for increasing astrocyte GSH production, and potentially, total antioxidant capacity in brain, via an NF-κB-dependent process.
authors.affiliation: Department of Biology and Program in Neuroscience, Syracuse University, Syracuse, New York.
authors.forename: Yan
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Jackman
authors.affiliation: Department of Biology and Program in Neuroscience, Syracuse University, Syracuse, New York.
authors.forename: Trista L
authors.initials: TL
authors.lastname: Thorn
authors.affiliation: Department of Biology and Program in Neuroscience, Syracuse University, Syracuse, New York.
authors.forename: Valarie E
authors.initials: VE
authors.lastname: Vought
authors.affiliation: Department of Biology and Program in Neuroscience, Syracuse University, Syracuse, New York.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Hewett
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D053583:Interleukin-1beta / Q000008:administration & dosage / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016877:Oxidants / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C587672:IL1B protein, mouse; C583355:IL1R1 protein, mouse; D053583:Interleukin-1beta; D016328:NF-kappa B; D016877:Oxidants; D017382:Reactive Oxygen Species; D053573:Receptors, Interleukin-1 Type I; D011994:Recombinant Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione
keywords: IL-1; central nervous system; glioprotection; neuroprotection; oxidative stress