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Papers In Press, published online ahead of print May 3, 2001
Division of Infection, Inflammation and Repair, University of Southampton, Southampton, Hampshire SO16 6YD
Corresponding Author: dam2{at}soton.ac.uk
Activation of hepatic stellate cells to a myofibroblast-like phenotype is the pivotal event in hepatic wound healing and fibrosis. Rat hepatic stellate cells activated in vitro express JunD, Fra2 and FosB as the predominant AP-1 DNA binding proteins and all three associate with an AP-1 sequence that is essential for activity of the tissue inhibitor of metalloproteinases-1 (TIMP-1) promoter. In this study we used expression vectors for wild type, dominant negative and forced homodimeric (Jun/eb1 chimeric factors) forms of JunD and other Fos and Jun proteins to determine the requirement for JunD in the transcriptional regulation of the TIMP-1 and interleukin-6 (IL-6) genes. JunD activity was required for TIMP-1 gene promoter activity, while over-expression of Fra2 or FosB caused a repression of promoter activity. The ability of homodimeric JunD/eb1 to elevate TIMP-1 promoter activity supports a role for JunD homodimers as the major AP-1 dependant trans-activators of the TIMP-1 gene. IL-6 promoter activity was induced with activation of hepatic stellate cells and also required JunD activity, however expression of JunD/eb1 homodimers resulted in transcriptional repression. Mutagenesis of the IL-6 promoter showed that an AP-1 DNA binding site previously reported to be an activator of transcription in fibroblasts functions as a suppressor of promoter activity in hepatic stellate cells. We conclude that JunD activates IL-6 gene transcription as a heterodimer and operates at an alternative DNA binding site in the promoter. The relevance of these findings to events occurring in the injured liver was addressed by showing that AP-1 DNA binding complexes are induced during HSC activation and contain JunD as the predominant Jun family protein. JunD is therefore an important transcriptional regulator of genes responsive to Jun homo and heterodimers in activated hepatic stellate cells.
J. Biol. Chem, 10.1074/jbc.M101840200
Submitted on February 28, 2001
Revised on May 3, 2001
Accepted on May 3, 2001
JunD regulates transcription of the tissue inhibitor of metalloproteinases-1 and interleukin-6 genes in activated hepatic stellate cells
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