Cellular and Molecular Neurobiology

, Volume 33, Issue 1, pp 19–30

Chronic Inflammation Alters Production and Release of Glutathione and Related Thiols in Human U373 Astroglial Cells

  • Megan L. Steele
  • Stacey Fuller
  • Annette E. Maczurek
  • Cindy Kersaitis
  • Lezanne Ooi
  • Gerald Münch
Original Research


Neurons rely on glutathione (GSH) and its degradation product cysteinylglycine released by astrocytes to maintain their antioxidant defences. This is particularly important under conditions of inflammation and oxidative stress, as observed in many neurodegenerative diseases including Alzheimer’s disease (AD). The effects of inflammatory activation on intracellular GSH content and the extracellular thiol profile (including cysteinylglycine and homocysteine) of astrocytes were investigated. U373 astroglial cells exposed to IL-1β and TNF-α for up to 96 h showed a dose-dependent increase in IL-6 release, indicative of increasing pro-inflammatory cellular activation. With increasing concentrations of IL-1β and TNF-α (0.01–1 ng/ml), an increase in both intracellular and extracellular GSH levels was observed, followed by a return to control levels in response to higher concentrations of IL-1β and TNF-α. Extracellular levels of cysteinylglycine decreased in response to all concentrations of IL-1β and TNF-α. In contrast, levels of the neurotoxic thiol homocysteine increased in a dose-dependent manner to IL-1β and TNF-α-induced activation. Our results suggest that chronically activated astrocytes in the brain might fail to adequately maintain GSH substrate delivery to neurons, thus promoting neuronal vulnerability. They might also explain the elevated levels of homocysteine found in the brains and serum of patients with AD.


Astrocyte Glutathione Cysteinylglycine Homocysteine Inflammation Alzheimer’s disease 





Alzheimer’s disease


Analysis of variance


Antioxidant response element


Cerebral spinal fluid


Dulbecco’s modified eagle medium


5,5′-Dithio-bis(2-nitrobenzoic acid)


Ethylenediaminetetraacetic acid


Enzyme-linked immunosorbent sandwich assay


Foetal bovine serum


Glutamate cysteine ligase




Glutathione disulfide


High performance liquid chromatography


Interleukin-1 beta




Kelch like-ECH-associated protein 1


Multidrug resistance protein 1


Reduced nicotinamide adenine dinucleotide phosphate




Nuclear factor erythroid-2-related factor 2


Parkinson’s disease


Reactive oxygen species


5-Thio-2-nitrobenzoic acid


Tumour necrosis factor-alpha




Catalytic glutamate cysteine ligase subunit


Modulatory glutamate cysteine ligase subunit


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Megan L. Steele
    • 1
    • 2
  • Stacey Fuller
    • 1
  • Annette E. Maczurek
    • 1
  • Cindy Kersaitis
    • 3
  • Lezanne Ooi
    • 1
  • Gerald Münch
    • 1
    • 4
  1. 1.Department of Pharmacology, School of MedicineUniversity of Western SydneyCampbelltownAustralia
  2. 2.School of Biochemistry and Molecular BiologyJames Cook UniversityTownsvilleAustralia
  3. 3.School of Science & HealthUniversity of Western SydneyCampbelltownAustralia
  4. 4.Molecular Medicine Research GroupUniversity of Western SydneyCampbelltownAustralia

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