Colonic epithelial cell activation and the paradoxical effects of butyrate

Butyrate may have paradoxical effects on epithelial cells of similar origin . This study aimed to examine the hypothesis that one mechanism that dictat es a cell's response to butyrate is its state of activation. First, the res ponses to 24 h exposure to butyrate (1-2 mM) of normal and neoplastic human colonic epithelial cells activated by their isolation and primary culture, and of colon cancer cell lines, LLM1215 and Caco-2, were examined, In prim ary cultures of normal and cancer cells, butyrate had no effect on alkaline phosphatase activities but significantly suppressed urokinase receptor exp ression by a mean +/- SEM of 30 +/- 12% and 36 +/- 9%, respectively, Interl eukin-8 secretion was suppressed by 44 +/- 7% in normal cells (P < 0.05) bu t was unchanged in cancer cells. In contrast, the cell lines significantly increased alkaline phosphatase activities by >50%, urokinase receptor expre ssion >2-fold and interleukin-8 secretion >3-fold in response to butyrate, Secondly, the effect of butyrate on Caco-2 cells was examined with or witho ut prior exposure to a specific activating stimulus [tumour necrosis factor alpha (TNF alpha)]. Interleukin-8 secretion increased by 145 +/- 23% and 1 32 +/- 17% on 24 h exposure to 2 mM butyrate or 0.1 mu M TNF alpha alone, r espectively. However, in cells pre-treated with TNF alpha, butyrate signifi cantly inhibited secretion by 34 +/- 7% below unstimulated levels. The resp onse to butyrate of urokinase receptor, whose expression was not stimulated by TNF alpha, was unchanged. These effects were mimicked by trichostatin A , an inhibitor of histone deacetylase, suggesting that butyrate's paradoxic al effects may have been operating by the same mechanism. In conclusion, so me of the paradoxical effects of butyrate do not appear to represent inhere nt differences between normal and transformed cells. Rather, the response m ay be determined by the state of activation of the cells.