BILE-ACIDS WITH DIFFERING HYDROPHILIC-HYDROPHOBIC PROPERTIES DO NOT INFLUENCE CYTOKINE PRODUCTION BY HUMAN MONOCYTES AND MURINE KUPFFER CELLS

Bile acids have been proposed to exert immunological effects of potent ial pathogenic or therapeutic relevance, yet the experimental evidence remains preliminary. We reexamined the effects of a variety of bile s alts with differing hydrophilic-hydrophobic properties on the producti on of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF alpha) from monocytes and Kupffer cells. Monocytes from healthy human donors and Kupffer cells from 5-week-old mice were incubated for up to 18 ho urs with or without varying concentrations of bile salts and lipopolys accharide (LPS). Monocyte viability was greater than or equal to 95% w ith up to 250 mu mol/L sodium ursodeoxycholate and mu 90% with 200 mu mol/L chenodeoxycholate, decreasing sharply at higher concentrations. Kupffer cells were more vulnerable, particularly to chenodeoxycholate (viabilities of 25% and 0% at concentrations of 100 mu mol/L and 200 m u mol/L, respectively). In monocytes incubated in the presence of 20% fetal calf serum, neither ursodeoxycholate and chenodeoxycholate, nor a variety of other unconjugated and conjugated bile acids, tested up t o their maximal noncytotoxic concentrations, influenced the IL-6 and T NF(alpha production, at any level of LPS stimulation. Similar to monoc ytes, incubation of murine Kupffer cells with ursodeoxycholate and che nodeoxycholate did not influence cytokine release. In contrast, the ad dition of 10 nmol/L dexamethasone to monocytes significantly decreased TNF-alpha and IL-6 release (69 +/- 11% and 48 +/- 15%, respectively). When monocytes were incubated with 200 mu mol/L chenodeoxycholate in the presence of lower concentrations of fetal calf serum (10% and 5%, respectively) a significant inhibition of cytokine release was observe d, whereas incubation with ursodeoxycholate did not cause any effect. Flow cytometry using fluoresceinated LPS showed that chenodeoxycholate does not interact with the CD14 receptor, thus excluding the possibil ity of an interference with the LPS uptake by monocytes. Incubation wi th [C-14]-chenodeoxycholate showed that the intracellular bile acid up take was inversely related to the concentration of fetal calf serum, b eing negligible (<3 fmol/cell) at the highest level. In conclusion, bi le acids with widely different hydrophobicities are incapable of influ encing the release of IL-6 and TNF alpha by monocytes and Kupffer cell s, provided they are studied at noncytotoxic concentrations and in the presence of physiological amounts of proteins.