Redox regulation of pro-inflammatory cytokines and IkappaB-alpha/NF-kappaB nuclear translocation and activation

Biochem Biophys Res Commun. 2002 Aug 30;296(4):847-56. doi: 10.1016/s0006-291x(02)00947-6.


Reduction-oxidation (redox) state constitutes such a potential signaling mechanism for the regulation of an inflammatory signal associated with oxidative stress. Exposure of alveolar epithelial cells to ascending DeltapO(2) regimen+/-reactive oxygen species (ROS)-generating systems induced a dose-dependent release of interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha. Similarly, the Escherichia coli-derived lipopolysaccharide-endotoxin (LPS) up-regulated cytokine biosynthesis in a dose- and time-dependent manner. Irreversible inhibition of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in the biosynthesis of glutathione (GSH), by L-buthionine-(S,R)-sulfoximine (BSO), induced the accumulation of ROS and augmented DeltapO(2) and LPS-mediated release of cytokines. Analysis of the molecular mechanism implicated revealed an inhibitory-kappaB (IkappaB-alpha)/nuclear factor-kappaB (NF-kappaB)-independent pathway in mediating redox-dependent regulation of inflammatory cytokines. BSO stabilized cytosolic IkappaB-alpha and down-regulated its phosphorylation, thereby blockading NF-kappaB activation, yet it augmented cytokine secretion. Glutathione depletion is associated with the augmentation of oxidative stress-mediated inflammatory state in a ROS-dependent mechanism and the IkappaB-alpha/NF-kappaB pathway is redox-sensitive but differentially involved in regulating redox-dependent regulation of cytokines.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Antioxidants / pharmacology
  • Blotting, Western
  • Cell Nucleus / metabolism*
  • Cells, Cultured
  • Cytokines / metabolism
  • DNA-Binding Proteins / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay
  • Epithelial Cells
  • Escherichia coli / metabolism
  • Glutamate-Cysteine Ligase / metabolism
  • Glutathione / metabolism
  • Hydrogen Peroxide / pharmacology
  • I-kappa B Proteins*
  • Interleukin-1 / metabolism
  • Interleukin-6 / metabolism
  • Lipopolysaccharides / metabolism
  • Lipopolysaccharides / pharmacology
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Oxidation-Reduction*
  • Oxidative Stress
  • Oxygen / metabolism
  • Protein Transport
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species
  • Signal Transduction
  • Temperature
  • Time Factors
  • Up-Regulation


  • Antioxidants
  • Cytokines
  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Interleukin-1
  • Interleukin-6
  • Lipopolysaccharides
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, rat
  • Reactive Oxygen Species
  • NF-KappaB Inhibitor alpha
  • Hydrogen Peroxide
  • Glutamate-Cysteine Ligase
  • Glutathione
  • Oxygen