Bile salts determine leukotriene B₄ synthesis in a human intestinal cell line (CaCo-2)

Abstract

The ability of a human colonic epithelial cell line (CaCo-2) to synthesize leukotriene B₄ (LTB₄) in response to bile salt stimulation was examined, as was the dependency of such stimulation on the hydrophobic-hydrophilic balance of the bile salts. We demonstrate for the first time in this human intestinal epithelial cell line the ability of bile salts to stimulate synthesis of LTB₄. CaCo-2 cell monolayers were incubated with a series of bile salts ranging in concentration from 0.5 µM to 1 mM. This resulted in a dose- and hydrophobicity-dependent increase in LTB₄ synthesis. Hydrophobic bile salts (glycine and taurine conjugates of lithocholate and deoxycholate) caused LTB₄ synthesis to be stimulated 27% and 35%, respectively, above control levels. In contrast, hydrophilic bile salts (glycine and taurine conjugates of ursodeoxycholate) increased LTB₄ synthesis only 11.2% and 16.1%. Under basal conditions pretreatment with dexamethasone significantly inhibited bile salt-induced LTB₄ synthesis by 38% compared to control. With more hydrophobic bile salts, chenodeoxycholate and deoxycholate, dexamethasone inhibited LTB₄ synthesis to levels significantly below those observed with dexamethasone under basal conditions. Unlike A23187 calcium ionophore-induced LTB₄ synthesis, bile salt-induced stimulation of LTB₄ synthesis was not found to be dependent on the presence of extracellular calcium. Variations in bile salt stimulation of LTB₄ by intestinal epithelial cells could be important in modulating cellular responses. The synthesis of chemotactic factors, such as LTB₄, by the human colonic adenocarcinoma epithelial cell line now needs to be extended to normal human intestinal epithelium, as it may play a role in many of the functional disturbances which characterize intestinal inflammatory conditions.