PT - JOURNAL ARTICLE AU - Birgit Fogal AU - Jun Li AU - Doug Lobner AU - Louise D. McCullough AU - Sandra J. Hewett TI - System x<sub>c</sub><sup>−</sup> Activity and Astrocytes Are Necessary for Interleukin-1β-Mediated Hypoxic Neuronal Injury AID - 10.1523/JNEUROSCI.2459-07.2007 DP - 2007 Sep 19 TA - The Journal of Neuroscience PG - 10094--10105 VI - 27 IP - 38 4099 - http://www.jneurosci.org/content/27/38/10094.short 4100 - http://www.jneurosci.org/content/27/38/10094.full SO - J. Neurosci.2007 Sep 19; 27 AB - The purpose of this study was to elucidate the cellular/biochemical pathway(s) by which interleukin-1β (IL-1β) contributes to the pathogenesis of hypoxic–ischemic brain damage. In vivo, IL-1 receptor type I (IL-1RI)-deficient mice showed smaller infarcts and less neurological deficits than wild-type animals after a 90 min reversible middle cerebral artery occlusion. In vitro, IL-1β mediated an enhancement of hypoxic neuronal injury in murine cortical cultures that was lacking in cultures derived from IL-1RI null mutant animals and was blocked by the IL-1 receptor antagonist or an IL-1RI blocking antibody. This IL-1β-mediated potentiation of hypoxic neuronal injury was associated with an increase in both cellular cystine uptake ([cystine]i) and extracellular glutamate levels ([glutamate]e) and was prevented by either ionotropic glutamate receptor antagonism or removal of l-cystine, suggesting a role for the cystine/glutamate antiporter (System xc−). Indeed, dual System xc−/metabotropic glutamate receptor subunit 1 (mGluR1) antagonism but not selective mGluR1 antagonism prevented neuronal injury. Additionally, cultures derived from mGluR1-deficient mice exhibited the same potentiation in injury after treatment with IL-1β as wild-type cultures, an effect prevented by System xc−/mGluR1 antagonism. Finally, assessment of System xc− function and kinetics in IL-1β-treated cultures revealed an increase in velocity of cystine transport (Vmax), in the absence of a change in affinity (Km). Neither the enhancement in [cystine]i, [glutamate]e, or neuronal injury were observed in chimeric cultures consisting of IL-1RI+/+ neurons plated on top of IL-1RI−/− astrocytes, highlighting the importance of astrocyte-mediated alterations in System xc− as a novel contributor to the development and progression of hypoxic neuronal injury.