Regulation of System xc- by Interleukin-1 beta

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DESCRIPTION (provided by applicant): Oxidative stress is a harmful condition that occurs when an imbalance between the production of reactive oxygen species (ROS) and the cellular defenses utilized to neutralize the toxic intermediates exists such that equilibrium is shifted in favor of ROS. Oxidative stress is involved in normal aging and a variety of diseases of the aged including Alzheimer's and Parkinson's disease and stroke. Recently, our laboratory has demonstrated in mixed cortical cell cultures that the cytokine interleukin-1beta (IL-1beta ) - which is upregulated in numerous neurological diseases/disorders - enhances the activity of the amino acid transporter system xc mediating an increase in cellular cyst(e)ine, a constituent of the tripeptide antioxidant molecule glutathione. Thus, the objective of this proposal is to elucidate the cellular, molecular, and biochemical mechanisms by which IL-1beta regulates system xc. In Aim 1, studies will identify the cell type or types in which the transporter is regulated. Using pure neuronal and astrocyte cultures and chimeric mixed cultures containing a combination of wild-type and system xc deficient cells, the specific hypothesis that IL-1beta enhances the activity of astrocytic system xc will be tested. Using numerous models of oxidative stress, the functional significance of this increase in activity will also be ascertained. In Aim 2, experiments will be performed to determine the mechanism by which IL-1beta regulates system xc. State of the art molecular biological approaches will be utilized to assess whether regulation occurs at the transcriptional and/or post-transcriptional level. Overall, the long-term objective of this project is to better understand how IL-1beta regulates the cystine-glutamate (system xc) transporter. A greater understanding of its regulation may enable researchers to target therapies to increase intracellular glutathione levels for the reduction of oxidative injury. PUBLIC HEALTH RELEVANCE: Oxidative stress is a harmful condition involved in both normal aging and a variety of neurological diseases/disorders of the aged. Strategies aimed at limiting and repairing the damage attributed to oxidative stress may slow the advance of many age-related diseases. Successful completion of this proposal will advance and refine our knowledge about an important new therapeutic target (system xc-) that complements other ongoing efforts to reduce injury associated with oxidative stress.