title: Reactive oxygen species from human astrocytes induced functional impairment and oxidative damage.
abstract: Reactive oxygen species (ROS) have been shown to be a contributor to aging and disease. ROS also serve as a trigger switch for signaling cascades leading to corresponding cellular and molecular events. In the central nervous system (CNS), microglial cells are likely the main source of ROS production. However, activated astrocytes also appear to be capable of generating ROS. In this study we investigated ROS production in human astrocytes stimulated with interleukin (IL)-1β and interferon (IFN)-γ and its potential harmful effects. Although IFN-γ alone had no effect, it potentiated IL-1β-induced ROS production in a time-dependent manner. One of the sources of ROS in IL-1β-activated astrocytes was from increased superoxide production in mitochondria accompanied by enhanced manganese superoxide dismutase and inhibited catalase expression. NADPH oxidase (NOX) may also contribute to ROS production as astrocytes express NOX isoforms. Glutamate uptake, which represents one of the most important methods of astrocytes to prevent excitotoxicity, was down-regulated in IL-1β-activated astrocytes, and was further suppressed in the presence of IFN-γ; IFN-γ itself exerted minimal effect. Elevated levels of 8-isoprostane in IL-1β ± IFN-γ-activated human astrocytes indicate downstream lipid peroxidation. Pretreatment with diphenyleneiodonium abolished the IL-1β ± IFN-γ-induced ROS production, restored glutamate uptake function and reduced 8-isoprostane to near control levels suggesting that ROS contributes to the dysfunction of activated astrocytes. These results support the notion that dampening activated human astrocytes to maintain the redox homeostasis is vital to preserve their neuroprotective potential in the CNS.
authors.affiliation: Department of Medicine, The Center for Infectious Diseases & Microbiology Translational Research (CIDMTR), University of Minnesota Medical School, Minneapolis, MN, 55455, USA, sheng008@umn.edu.
authors.forename: Wen S
authors.initials: WS
authors.lastname: Sheng
authors.forename: Shuxian
authors.initials: S
authors.lastname: Hu
authors.forename: Amy
authors.initials: A
authors.lastname: Feng
authors.forename: R Bryan
authors.initials: RB
authors.lastname: Rock
mesh_terms: D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D004357:Drug Synergism; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: C573415:IFNG protein, human; D053583:Interleukin-1beta; D009861:Onium Compounds; D017382:Reactive Oxygen Species; C075750:8-epi-prostaglandin F2alpha; D018698:Glutamic Acid; C007517:diphenyleneiodonium; D007371:Interferon-gamma; D015237:Dinoprost; D019255:NADPH Oxidases
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