Inhibition by deacetylase inhibitors of IL-1-Dependent induction of haptoglobin involves CCAAT/Enhancer-Binding protein isoforms in intestinal epithelial cells

Intestinal epithelial cells participate in an acute phase response (APR) by responding to cytokines and by expressing acute phase protein genes. We hypothesized that butyrate, a fermentation product of the bacterial intestinal flora with deacetylase activity, affects the APR in intestinal epithelial cells. Sodium butyrate (NaBu) and Trichostatin A (TSA) induced alkaline phosphatase activity and histone H4 acetylation in IEC-6 rat intestinal epithelial cells treated with or without interleukin-1 beta (IL-1). In contrast, both NaBu and TSA attenuated the IL-1-dependent induction of the acute phase protein gene haptoglobin, as well as C/EBP beta and C/EBP delta transcription factors mRNAs. Gel shift and supershift assays showed a strong decrease in the IL-1-induced C/EBP beta and C/EBP delta containing complexes binding to the HaptoA C/EBP DNA-binding site of the haptoglobin promoter, by NaBu and TSA. Furthermore, site-specific mutation of the HaptoA site abolished the NaBu- and TSA-dependent inhibition of haptoglobin, as determined by transient transfection assays. These results suggest that deacetylase inhibitors may regulate the IL-1 dependent induction of haptoglobin by down-regulating C/EBP isoforms, and that C/EBPs represent a target for the action of butyrate in the control of the APR of intestinal epithelial cells. (C) 2000 Academic Press.