INHIBITION OF PROCOAGULANT ACTIVITY OF HUMAN MONOCYTES BY CHENODEOXYCHOLIC ACID - INVOLVEMENT OF PROTEIN-KINASE-C

Endogenous bile acids such as chenodeoxycholic acid have been shown to display a suppressive effect in vitro on mononuclear cell activation, We investigated the signal transduction pathway involved in the effec t of chenodeoxycholic acid on monocyte procoagulant activity, a model of monocyte activation. Chenodeoxycholic acid (25 to 250 mu mol/L) had a concentration-dependent inhibitory effect on procoagulant activity expressed by endotoxin-stimulated mononuclear cells, with half-maximal and maximal inhibition occurring at concentrations of 100 and 250 mu mol/L, respectively. The inhibitory effect of chenodeoxycholic acid wa s (a) closely mimicked by 4 beta-phorbol 12 beta-myristate 13 alpha-ac etate (PMA), a protein kinase C activator, but not by forskolin or dib utyryl cyclic AMP, two activators of the protein kinase A-dependent pa thway; (b) prevented by staurosporine, a potent protein kinase C inhib itor; (c) partially abolished in protein kinase C-depleted cells; and (d) observed in conditions under which chenodeoxycholic acid, like PMA , significantly increased (41%) protein kinase C activity, as assessed by phosphorylation of exogenous (histone III-S) and endogenous (37-kD protein) substrates. In conclusion, our results (a) provide clear evi dence of a marked inhibitory effect of chenodeoxycholic acid on monocy te activation, suggesting a potential role of primary endogenous bile acids in the immune defect associated with cholestasis; and (b) indica te that the inhibition of monocyte activation by chenodeoxycholic acid is mediated by way of protein kinase C activation.