Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages

J Biol Chem. 2000 May 26;275(21):16023-9. doi: 10.1074/jbc.275.21.16023.


Electrophiles and reactive oxygen species have been implicated in the pathogenesis of many diseases. Transcription factor Nrf2 was recently identified as a general regulator of one defense mechanism against such havoc. Nrf2 regulates the inducible expression of a group of detoxication enzymes, such as glutathione S-transferase and NAD(P)H:quinone oxidoreductase, via antioxidant response elements. Using peritoneal macrophages from Nrf2-deficient mice, we show here that Nrf2 also controls the expression of a group of electrophile- and oxidative stress-inducible proteins and activities, which includes heme oxygenase-1, A170, peroxiredoxin MSP23, and cystine membrane transport (system x(c)(-)) activity. The response to electrophilic and reactive oxygen species-producing agents was profoundly impaired in Nrf2-deficient cells. The lack of induction of system x(c)(-) activity resulted in the minimum level of intracellular glutathione, and Nrf2-deficient cells were more sensitive to toxic electrophiles. Several stress agents induced the DNA binding activity of Nrf2 in the nucleus without increasing its mRNA level. Thus Nrf2 regulates a wide-ranging metabolic response to oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Female
  • Gene Expression Regulation*
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Heme Oxygenase (Decyclizing) / genetics
  • Heme Oxygenase (Decyclizing) / metabolism
  • Heme Oxygenase-1
  • Macrophages, Peritoneal / enzymology
  • Macrophages, Peritoneal / metabolism*
  • Membrane Proteins
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • NF-E2-Related Factor 2
  • Oxidants / pharmacology
  • Oxidative Stress / genetics*
  • Peroxidases*
  • Peroxiredoxins
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / metabolism
  • Sequestosome-1 Protein
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*


  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • Heat-Shock Proteins
  • Membrane Proteins
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Oxidants
  • RNA, Messenger
  • Reactive Oxygen Species
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • Trans-Activators
  • Peroxidases
  • Peroxiredoxins
  • Prdx1 protein, mouse
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • Hmox1 protein, mouse