Date of Completion

5-8-2013

Embargo Period

5-8-2014

Keywords

interleukin-1, cystine, glutamate, astrocyte, glutathione

Major Advisor

Sandra Hewett

Associate Advisor

Stephen Crocker

Associate Advisor

Betty Eipper

Associate Advisor

Louise McCullough

Associate Advisor

James Hewett

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

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.

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