Abstract
Interleukin-1β (IL-1β), a key cytokine that drives neuroinflammation in the Central Nervous System (CNS), is enhanced in many neurological diseases/disorders. Although IL-1β contributes to and/or sustains pathophysiological processes in the CNS, we recently demonstrated that IL-1β can protect cortical astrocytes from oxidant injury in a glutathione (GSH)-dependent manner. To test whether IL-1β could similarly protect neurons against oxidant stress, near pure neuronal cultures or mixed cortical cell cultures containing neurons and astrocytes were exposed to the organic peroxide, tert-butyl hydroperoxide (t-BOOH), following treatment with IL-1β or its vehicle. Neurons and astrocytes in mixed cultures, but not pure neurons, were significantly protected from the toxicity of t-BOOH following treatment with IL-1β in association with enhanced GSH production/release. IL-1β failed to increase the GSH levels or to provide protection against t-BOOH toxicity in chimeric mixed cultures consisting of IL-1R1+/+ neurons plated on top of IL-1R1−/− astrocytes. The attenuation of GSH release via block of multidrug resistance-associated protein 1 (MRP1) transport also abrogated the protective effect of IL-1β. These protective effects were not strictly an in vitro phenomenon as we found an increased striatal vulnerability to 3-nitropropionic acid-mediated oxidative stress in IL-1R1 null mice. Overall, our data indicate that IL-1β protects neurons against oxidant injury and that this likely occurs in a non-cell-autonomous manner that relies on an increase in astrocyte GSH production and release.
Highlights
Interleukin 1β and its signaling receptor IL-1R1 are expressed at low levels in the healthy brain, where they participate in normal brain function, including learning and memory
We determined that the IL-1β treatment of primary astrocytes enhanced their production and release of GSH, rendering them resistant to death induced by exposure to the organic peroxide, tert-butyl hydroperoxide (t-BOOH) [12]
The present results demonstrate that IL-1β protects neurons against oxidant injury both in vitro and in vivo and that this likely occurs in a non-cell-autonomous manner that relies on an increase in and in vivo and that this likely occurs in a non-cell-autonomous manner that relies on an increase astrocyte GSH production and release
Summary
Interleukin 1β and its signaling receptor IL-1R1 are expressed at low levels in the healthy brain, where they participate in normal brain function, including learning and memory. There is a direct indication of the role of IL-1 signaling in the regulation of sleep and sleep patterning in both rodents and humans [4,5,6]. An impressive amount of literature supports its role in Central Nervous System (CNS) pathology, a clear cause-and-effect relationship between the presence of this neuroinflammatory factor and CNS damage does not always exist (for review see: [7]). It is becoming increasingly clear that IL-1β can protect and repair CNS tissue (for review see Reference [7]). The Janus face of IL-1β may depend heavily on the context, that is, its concentration and timing, its cellular target(s), and the presence or absence of negative feedback regulators.
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