Hepatic stellate cells lack AP-1 responsiveness to electrophiles and phorbol 12-myristate-13-acetate.
Stellate cell profibrotic gene induction and transdifferentiation are central events in liver fibrosis. Oxidative stress has been implicated as an activator of the transcription factors Nrf2 and AP-1 through shared kinase signaling pathways that also purportedly contribute to stellate cell activation. The present study examined the role of oxidative stress in ARE- and TRE-regulated gene induction in isolated hepatic stellate cells. Using a portion of the human Nqo1 promoter consisting of an ARE imbedded TRE, it was demonstrated that while the ARE was responsible for mediating inducible gene expression in response to the electrophiles 4-HNE and tBHQ, the TRE was refractory to induction by either electrophiles or PMA. It was demonstrated that stellate cells possess nuclear TRE-binding proteins that were identified as JunB, JunD, Fra1, and Fra2, which were unaffected by either electrophiles or PMA treatment. This report demonstrates that, in contrast to the ARE, the TRE and its binding cognate AP-1 did not mediate independent gene induction in hepatic stellate cells. This observation is significant given the presumed importance attributed to AP-1 in mediating profibrogenic gene expression.
Reichard
John F
JF
Department of Pharmaceutical Sciences, Molecular Toxicology and Environmental Health Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Petersen
Dennis R
DR
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001483:Base Sequence; D002478:Cells, Cultured; D016384:Consensus Sequence; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D006873:Hydroquinones / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008103:Liver Cirrhosis / Q000473:pathology; D016296:Mutagenesis; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016415:Sequence Alignment; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
D000975:Antioxidants; D006873:Hydroquinones; D018808:Transcription Factor AP-1; C018855:2-tert-butylhydroquinone; D013755:Tetradecanoylphorbol Acetate