Inhibition of procoagulant activity of human monocytes by chenodeoxycholic acid: Involvement of protein kinase C

Abstract

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 effect of chenodeoxycholic acid on monocyte procoagulant activity, a model of monocyte activation. Chenodeoxycholic acid (25 to 250 μmol/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 μmol/L, respectively. The inhibitory effect of chenodeoxycholic acid was (a) closely mimicked by 4β‐phorbol 12β‐myristate 13α‐acetate (PMA), a protein kinase C activator, but not by forskolin or dibutyryl cyclic AMP, two activators of the protein kinase A‐dependent pathway; (b) prevented by staurosporine, a potent protein kinase C inhibitor; (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 evidence of a marked inhibitory effect of chenodeoxycholic acid on monocyte activation, suggesting a potential role of primary endogenous bile acids in the immune defect associated with cholestasis; and (b) indicate that the inhibition of monocyte activation by chenodeoxycholic acid is mediated by way of protein kinase C activation (HEPATOLOGY 1994;19:1164–1170.) Copyright © 1994 American Association for the Study of Liver Diseases