Oxidative stress and inflammation modulate Rev-erb? signaling in the neonatal lung and affect circadian rhythmicity.

ABSTRACT: 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-erb?, a key circadian gene, was regulated by oxidative stress and/or inflammation in vitro and in a mouse model.A unique sequence consisting of overlapping AP-1 and nuclear factor kappa B (NF?B) consensus sequences was identified on the mouse Rev-erb? promoter. This sequence mediates Rev-erb? 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-erb?, as well as an NF?B-binding site to repress Rev-erb? with inflammatory stimuli. The amplitude of the rhythmicity of Rev-erb? was altered by pre-exposure to hyperoxia or disruption of NF?B in a cell culture model of circadian simulation. Oxidative stress overcame the inhibitory effect of NF?B binding on Rev-erb? transcription. This was confirmed in neonatal mice exposed to hyperoxia, where hyperoxia-induced lung Rev-erb? transcription was further increased with NF?B disruption. Interestingly, this effect was not observed in similarly exposed adult mice.These data provide novel mechanistic insights into how key circadian genes are regulated by oxidative stress and inflammation in the neonatal lung.Rev-erb? transcription and circadian oscillation are susceptible to oxidative stress and inflammation in the neonate. Due to Rev-erb?'s role in cellular metabolism, this could contribute to lung cellular function and injury from inflammation and oxidative stress.

SUBMITTER: Yang G 

PROVIDER: S-EPMC4048579 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature