SUPPRESSION OF STELLATE CELL-TYPE-I COLLAGEN GENE-EXPRESSION INVOLVESAP-2 TRANSMODULATION OF NUCLEAR FACTOR-1-DEPENDENT GENE-TRANSCRIPTION

The regulation of collagen gene expression was studied in culture-acti vated rat hepatic stellate cells, the fibrogenic effector cell involve d in hepatic fibrogenesis, Treatment of cells with a 5-lipoxygenase-sp ecific inhibitor caused a reduction in alpha I(I) collagen mRNA transc ript abundance, which suggested that leukotriene production was involv ed in maintaining the activated cell's high level of collagen mRNA pro duction. The underlying mechanism involved a decrease in collagen gene transcription, Suppression of gene transcription was localized to an nuclear factor-1 (NF-1) binding domain in the proximal promoter and an AP-2 binding domain adjacent to it, Gel retardation assays demonstrat ed that an increase in AP-2 binding adjacent to the NF-1 site was like ly to be the transmodulator responsible for the suppression of the NF- 1-dependent gene expression. The data suggest that post translational alterations in AP-2 activity are responsible for this unappreciated me chanism of regulating the collagen gene.