Nrf2 regulates the sensitivity of death receptor signals by affecting intracellular glutathione levels

Naoki Morito, Keigyou Yoh, Ken Itoh, Aki Hirayama, Akio Koyama, Masayuki Yamamoto, Satoru Takahashi

Research output: Contribution to journalArticlepeer-review

89 Citations (Scopus)

Abstract

Nrf2 is a basic leucine zipper transcriptional activator that is essential for the coordinate transcriptional induction of various antioxidant drug-metabolizing enzymes. Numerous studies have firmly established Nrf2's importance in protection from oxidative stress and certain chemical insults. Given the protective function of Nrf2, surprisingly few studies have focused on the relationship between Nrf2 and apoptosis. Therefore, we analysed how Nrf2 influences Fas signaling using Nrf2-deficient T cells. At a concentration of 1 μg/ml, the anti-Fas antibody induced 60% of cell death in Nrf2-deficient cultured thymocytes while, using the same treatment, only 40% of Nrf2 wild-type thymocytes died (P < 0.05). Nrf2 deficiency enhances the sensitivity of Fas-mediated apoptosis in T cells. Next we examined the effect of Nrf2 deficiency during hepatocellular apoptosis in vivo. In comparison to wild-type mice, Nrf2-deficient mice displayed more severe hepatitis after induction with the anti-Fas antibody or tumor necrosis factor (TNF)-α. The enhanced sensitivity to anti-Fas or TNF-α stimulation was restored by preadministration of glutathione ethyl monoester, a compound capable of passing the cell membrane and upregulating the intracellular levels of glutathione. The results indicated that Nrf2 activity regulates the sensitivity of death signals by means of intracellular glutathione levels.

Original languageEnglish
Pages (from-to)9275-9281
Number of pages7
JournalOncogene
Volume22
Issue number58
DOIs
Publication statusPublished - 2003 Dec 18
Externally publishedYes

Keywords

  • Apoptosis
  • Fas
  • Nrf2
  • Oxidative stress
  • TNF-receptor I

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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