Tumor necrosis factor alpha (TNFalpha) induces the unfolded protein response (UPR) in a reactive oxygen species (ROS)-dependent fashion, and the UPR counteracts ROS accumulation by TNFalpha

J Biol Chem. 2005 Oct 7;280(40):33917-25. doi: 10.1074/jbc.M505818200. Epub 2005 Aug 17.


Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER overload, resulting in ER stress. To cope with ER stress, mammalian cells trigger a specific response known as the unfolded protein response (UPR). Although recent studies have indicated cross-talk between ER stress and oxidative stress, the mechanistic link is not fully understood. By using murine fibrosarcoma L929 cells, in which tumor necrosis factor (TNF) alpha induces accumulation of reactive oxygen species (ROS) and cell death, we show that TNFalpha induces the UPR in a ROS-dependent fashion. In contrast to TNFalpha, oxidative stresses by H2O2 or arsenite only induce eukaroytic initiation factor 2alpha phosphorylation, but not activation of PERK- or IRE1-dependent pathways, indicating the specificity of downstream signaling induced by various oxidative stresses. Conversely, the UPR induced by tunicamycin substantially suppresses TNFalpha-induced ROS accumulation and cell death by inhibiting reduction of cellular glutathione levels. Collectively, some, but not all, oxidative stresses induce the UPR, and pre-emptive UPR counteracts TNFalpha-induced ROS accumulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arsenites / pharmacology
  • Blotting, Northern
  • Blotting, Western
  • Cell Death
  • Endoplasmic Reticulum / physiology
  • Fibrosarcoma / pathology
  • Glutathione / metabolism
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Mice
  • Oxidants / pharmacology
  • Protein Denaturation*
  • Reactive Oxygen Species / metabolism*
  • Reactive Oxygen Species / pharmacology*
  • Recombinant Proteins
  • Signal Transduction
  • Teratogens / pharmacology
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / physiology*


  • Arsenites
  • Oxidants
  • Reactive Oxygen Species
  • Recombinant Proteins
  • Teratogens
  • Tumor Necrosis Factor-alpha
  • Hydrogen Peroxide
  • Glutathione
  • arsenite