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

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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.