Bile acid-induced inhibition of the lymphoproliferative response to phytohemagglutinin and pokeweed mitogen: an in vitro study

The effects of free and conjugated bile acids on the lymphoproliferative response to phytohemagglutinin (PHA) or pokeweed mitogen (PWM) have been investigated in vitro. Significant inhibition of lymphocyte transformation was observed with 250 mumol/liter of either chenodeoxycholic (CDCA) or cholic acid (CA); the former caused more pronounced inhibition at higher concentrations. This was true whichever mitogen was present. Conjugated bile acids caused lesser degrees of inhibition than the respective free bile acids and the glycoconjugates were more inhibitory than the respective tauroconjugates of the same bile acid. At concentrations of free bile acids which completely suppressed lymphocyte transformation, no cytotoxic effects or impairment of cell viability were detected. Since the concentrations that inhibited the lymphoproliferative response were markedly lower than those reported to induce cell membrane damage, the activity observed can be attributed to a metabolic effect within the cell. Inhibition by bile acids of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activity, resulting in a reduction of the endogenous cholesterol synthesis required for cell growth and proliferation, might account for our observations. Our results contribute to understanding the nature of the serum-dependent inhibition of lymphocyte transformation reported to exist in cholestatic liver disease.