Oxidative stress and inflammation modulate Rev-erbα signaling in the neonatal lung and affect circadian rhythmicity

Antioxid Redox Signal. 2014 Jul 1;21(1):17-32. doi: 10.1089/ars.2013.5539. Epub 2014 Mar 14.


Aims: The response to oxidative stress and inflammation varies with diurnal rhythms. Nevertheless, it is not known whether circadian genes are regulated by these stimuli. We evaluated whether Rev-erbα, a key circadian gene, was regulated by oxidative stress and/or inflammation in vitro and in a mouse model.

Results: A unique sequence consisting of overlapping AP-1 and nuclear factor kappa B (NFκB) consensus sequences was identified on the mouse Rev-erbα promoter. This sequence mediates Rev-erbα promoter activity and transcription in response to oxidative stress and inflammation. This region serves as an NrF2 platform both to receive oxidative stress signals and to activate Rev-erbα, as well as an NFκB-binding site to repress Rev-erbα with inflammatory stimuli. The amplitude of the rhythmicity of Rev-erbα was altered by pre-exposure to hyperoxia or disruption of NFκB in a cell culture model of circadian simulation. Oxidative stress overcame the inhibitory effect of NFκB binding on Rev-erbα transcription. This was confirmed in neonatal mice exposed to hyperoxia, where hyperoxia-induced lung Rev-erbα transcription was further increased with NFκB disruption. Interestingly, this effect was not observed in similarly exposed adult mice.

Innovation: These data provide novel mechanistic insights into how key circadian genes are regulated by oxidative stress and inflammation in the neonatal lung.

Conclusion: Rev-erbα transcription and circadian oscillation are susceptible to oxidative stress and inflammation in the neonate. Due to Rev-erbα's role in cellular metabolism, this could contribute to lung cellular function and injury from inflammation and oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Binding Sites
  • Cell Survival / drug effects
  • Cells, Cultured
  • Circadian Rhythm / drug effects*
  • Comet Assay
  • DNA Damage / drug effects
  • Hydrogen Peroxide / pharmacology*
  • Lung / drug effects
  • Lung / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / genetics
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / metabolism*
  • Oxidative Stress / drug effects*
  • RNA, Messenger
  • Signal Transduction / drug effects


  • NF-kappa B
  • Nr1d1 protein, mouse
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • RNA, Messenger
  • Hydrogen Peroxide