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

Astrocytes produce and export the antioxidant glutathione (GSH). Previously, we found that interleukin-1 (IL-1) enhanced the expression of astrocyte system x(c)(-), the transporter that delivers the rate-limiting substrate for GSH synthesiscyst(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. GLIA 2015;63:1568-1580