Hepatic stellate cells lack AP-1 responsiveness to electrophiles and phorbol 12-myristate-13-acetate

Biochemical and Biophysical Research Communications
John F Reichard, Dennis R Petersen

Abstract

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.

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Citations

Aug 10, 2010·Apoptosis : an International Journal on Programmed Cell Death·Prabakaran RavichandranGovindarajan T Ramesh
Jul 8, 2014·Oxidative Medicine and Cellular Longevity·Antonio AyalaSandro Argüelles
Oct 8, 2014·Inflammation Research : Official Journal of the European Histamine Research Society ... [et Al.]·Xiaohui LiJun Li
Oct 20, 2005·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Leigh A WilsonGurmit Singh

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