BILE-SALTS DETERMINE LEUKOTRIENE B-4 SYNTHESIS IN A HUMAN INTESTINAL-CELL LINE (CACO-2)

The ability of a human colonic epithelial cell line (CaCo-2) to synthesize leukotriene B-4 (LTB(4)) 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 LTB(4). CaCo-2 cell monolayers were incubated with a series of bib salts ranging in concentration from 0.5 mu M to 1 mM. This resulted in a dose- and hydrophobicity-dependent increase in LTB(4) synthesis. Hydrophobic bile salts (glycine and taurine conjugates of lithocholate and deoxycholate caused LTB(4) synthesis to be stimulated 27% and 35%, respectively, above control levels. In contrast, hydrophilic bile salts (glycine and taurine conjugates of ursodeoxycholate) increased LTB(4) synthesis only 11.2% and 16.1%. Under basal conditions pretreatment with dexamethasone significantly inhibited bile salt-induced LTB(4) synthesis by 38% compared to control. With more hydrophobic bile salts, chenodeoxlycholate and deoxycholate, dexamethasone inhibited LTB(4) synthesis to levels significantly below those observed with dexamethasone under basal conditions. Unlike A23187 calcium ionophore-induced LTB(4) synthesis, bile salt-induced stimulation of LTB(4) synthesis was not found to be dependent on the presence of extracellular calcium. Variations in bile salt stimulation of LTB(4) by intestinal epithelial cells could be important in modulating cellular responses. The synthesis of chemotactic factors, such as LTB(4) 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.