Interleukin-1? protects astrocytes against oxidant-induced injury via an NF-?B-dependent upregulation of glutathione synthesis.

ABSTRACT: Astrocytes produce and export the antioxidant glutathione (GSH). Previously, we found that interleukin-1? (IL-1?) 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-1? 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-?B (NF-?B) 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-1? 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-1?, an effect reversed by concomitant exposure to l-buthionine-S,R-sulfoximine (BSO), which prevented the IL-1?-mediated rise in GSH production. IL-1? 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-1? may be an important stimulus for increasing astrocyte GSH production, and potentially, total antioxidant capacity in brain, via an NF-?B-dependent process.

SUBMITTER: He Y 

PROVIDER: S-EPMC4506211 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature