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 effect of chenodeoxycholic acid on monocyte procoagulant activity, a model of monocyte activation. Chenodeoxycholic acid (25 to 250 mumol/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 mumol/L, respectively. The inhibitory effect of chenodeoxycholic acid was (a) closely mimicked by 4 beta-phorbol 12 beta-myristate 13 alpha-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.
Podevin
P
P
INSERM U181, Hôpital Saint-Antoine, Paris, France.
Calmus
Y
Y
Robert
A
A
Poupon
R
R
Cherqui
G
G
D000470:Alkaloids / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects*; D003994:Bucladesine / Q000494:pharmacology; D002635:Chenodeoxycholic Acid / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000470:Alkaloids; D002635:Chenodeoxycholic Acid; D005576:Colforsin; D003994:Bucladesine; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate