Characterization of System xc -, a Cystine-Glutamate Amino Acid Transporter, as an Effector of Interleukin-1β-Mediated Injury and Neuroprotection
Date of Completion
interleukin-1, cystine, glutamate, astrocyte, glutathione
Field of Study
Doctor of Philosophy
Interleukin-1β (IL-1β) is a key mediator in the inflammatory response essential to cellular defense against pathogen invasion and to the repair of tissue damage. While some studies suggest that IL-1β signaling is harmful to the injured central nervous system, others report neuroprotective effects that appear to be context-dependent. Previously, the Hewett laboratory demonstrated IL-1β-mediated increases in the cystine-glutamate transporter, system xc-, as a novel contributor to inflammatory hypoxic neuronal injury. The focus of this doctoral research was to elucidate the specific cell type(s) in mixed cortical cultures that respond to IL-1β by enhancing the activity of system xc-, the molecular mechanism by which this occurs, and the physiological and pathophysiological consequences of this regulation. IL-1β exposure enhances expression of the substrate-specific light chain of system xc-, xCT, in astrocyte cultures in a time-dependent manner. By utilizing pharmacological inhibitors and cells derived from animals harboring a mutation in the Slc7a11 gene (sut mice) that encodes for xCT, we provide evidence that alterations in system xc- activity in astrocytes exclusively mediate the potentiation of hypoxic neuronal injury by IL-1β and initiates hypoglycemic neuronal injury. Even though the IL-1β-mediated enhanced efflux of glutamate, which occurs by virtue of its obligate exchange, can be deleterious, cystine import via system xc- is critical for the synthesis of the antioxidant glutathione (GSH). Since astrocytes function as the predominant provider of GSH in the CNS, we assessed whether IL-1β treatment altered astrocyte GSH levels. Cortical astrocyte cultures treated with IL-1β exhibit a time-dependent increase in extracellular GSH levels, suggesting both enhanced synthesis and export that is associated with protection against oxidative stress in cultures exposed to tert-butyl hydroperoxide. Hence, IL-1β may be an important stimulus for increasing astrocytic GSH production, and thus, total antioxidant capacity in the brain. These findings unequivocally demonstrate that IL-1β and astrocytic system xc- contribute to neuronal injury and neuroprotection in a context-dependent manner.
Jackman, Nicole A., "Characterization of System xc -, a Cystine-Glutamate Amino Acid Transporter, as an Effector of Interleukin-1β-Mediated Injury and Neuroprotection" (2013). Doctoral Dissertations. 60.