Glutathione depletion is associated with augmenting a proinflammatory signal: evidence for an antioxidant/pro-oxidant mechanism regulating cytokines in the alveolar epithelium

Cytokines Cell Mol Ther. 2000 Dec;6(4):177-87. doi: 10.1080/mccm.6.4.177.187.

Abstract

Chemioxyexcitation [deltapO2/reactive oxygen species (ROS)] constitutes a potential signaling mechanism for regulating an inflammatory signal associated with oxidative stress. Exposure of fetal alveolar type II epithelial cells to an ascending deltaPO2 regimen with or without the hydroxyl radical (OH) or the superoxide radical anion (O2*-) induces a dose-dependent release of pro-inflammatory cytokines. Similarly, the Escherichia coli-derived lipopolysaccharide (LPS) upregulates cytokine biosynthesis in a dose- and time-dependent manner. Irreversible inhibition by L-buthionine-(S,R)-sulfoximine (BSO) of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in the biosynthesis of glutathione (GSH), induces intracellular accumulation of ROS and augments chemioxyexcitation and LPS-mediated release of interleukin (IL)-1beta, IL-6, and tumor necrosis factor alpha (TNF-alpha). Analysis of the molecular mechanism implicated reveals an inhibitory kappaB (IkappaB-alpha)/nuclear factor kappaB (NF-kappaB)-independent pathway mediating the redox-dependent regulation of inflammatory cytokines. Although BSO stabilizes cytosolic IkappaB-alpha and downregulates its phosphorylation, thereby blockading NF-kappaB activation, it augments cytokine biosynthesis in a dose-dependent manner. These results indicate that glutathione depletion is associated with augmentation of an oxidative stress-mediated pro-inflammatory state in an ROS-dependent mechanism and that the IkappaB-alpha/NF-kappaB pathway is otherwise not necessarily indispensable for redox-mediated regulation of cytokines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anions
  • Antioxidants / pharmacology*
  • Blotting, Western
  • Buthionine Sulfoximine / pharmacology
  • Cells, Cultured
  • Cytokines / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Enzyme-Linked Immunosorbent Assay
  • Epithelium / metabolism*
  • Escherichia coli / metabolism
  • Glutamate-Cysteine Ligase / pharmacology
  • Glutathione / metabolism*
  • Hydrogen Peroxide / pharmacology
  • Inflammation / metabolism*
  • Interleukin-1 / metabolism
  • Interleukin-6 / metabolism
  • Lipopolysaccharides / metabolism
  • NF-kappa B / metabolism
  • Oxidation-Reduction
  • Pulmonary Alveoli / embryology
  • Pulmonary Alveoli / metabolism*
  • Rats
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Anions
  • Antioxidants
  • Cytokines
  • Enzyme Inhibitors
  • Interleukin-1
  • Interleukin-6
  • Lipopolysaccharides
  • NF-kappa B
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • Buthionine Sulfoximine
  • Hydrogen Peroxide
  • Glutamate-Cysteine Ligase
  • Glutathione