Butyrate, a primary source of energy for colonocytes, inhibits histone deacetylase and the process of colon carcinogenesis.  Butyrate regulates gene expression in intestinal epithelial cells.  For example, we have shown that butyrate modulates the expression of the c-myc and c-fos proto-oncogenes in intestinal epithelial cells.  Intestinal epithelial cells are an integral component of the mucosal immune system and participate in the acute phase response.  We hypothesized that butyrate may affect the intestinal epithelial cell response to cytokines during the acute phase response.  Methods: Expression of the acute phase response protein gene haptoglobin in the rat intestinal epithelial cell line IEC-6, and of serum amyloid A (SAA) in the colon carcinoma cell line Caco-2 was analysed by Northern blot in response to IL-1 with or without sodium butyrate or the specific deacetylase inhibitor Trichostatin (TSA).  Expression of C/EBP isoforms, transcription factors involved in APP gene expression, was assessed by Northern blot and electrophoretic mobility shift assays.  Results: Deacetylase inhibitors attenuated the IL-1 mediated induction of haptoglobin and SAA in IEC-6 and Caco-2 cells respectively.  In addition, butyrate and TSA reduced IL-1-dependent increases in C/EBPß and C/EBPd mRNA levels.  Interestingly, deacetylase inhibitors had no effect on non-induced C/EBP isoform mRNA levels.  Electrophoretic mobility shift assays showed that deacetylase inhibitors decreased the IL-1 dependent binding of C/EBP isoforms to a C/EBP DNA-binding site.  Conclusions: These results suggest that butyrate may negatively regulate the response of intestinal epithelial cells to cytokines by down-regulating C/EBP isoforms.  Supported by the MRC of Canada.

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