CCAAT enhancer binding proteins beta and delta regulate α1-acid glycoprotein gene expression in rat intestinal epithelial cells

Isoforms of CCAAT/enhancer binding protein (C/EBP) are expressed in rodent intestine as well as in the rat intestinal epithelial cell line IEC-6, However, no specific roles have been attributed to these isoforms in intestinal epithelial cells, To determine whether C/EBP family members could be implicated in the regulation of acute-phase response gene expression in intestinal epithelial cells, we have studied the effect of glucocorticoids on expression of the alpha(1)-acid glycoprotein gene and C/EBP isoforms in IEC-6 cells. Glucocorticoids induced alpha(1)-acid glycoprotein gene expression in these cells. This induction coincided with an increase of DNA-binding capacity of both C/EBP beta and C/EBP delta to the B1 and B2 C/EBP-interacting sites localized in the rat AGP promoter. Transforming growth factor beta, (TGF beta), a cytokine involved in the transcriptional regulation of several acute-phase plasma proteins, antagonized the glucocorticoid-dependent induction of alpha(1)-acid glycoprotein gene expression. In parallel, TGF beta downregulated the DNA-binding capacities of both the C/EBP beta and C/EBP delta isoforms, Mutations of the B1 or the B2 C/EBP-interacting site strongly reduced the responsiveness of the alpha 1-acid glycoprotein promoter to glucocorticoids and TGF beta, These results demonstrate a functional role for C/EBP beta and C/EBP beta in rat intestinal epithelial cells and suggest that these isoforms represent important modulators of the acute-phase response and of glucocorticoid, as well as TGF beta, responsiveness.