Interleukin-6 (IL-6) is a major regulator of the
acute phase reaction in the liver and is thought to mediate protective effects in response to hepatotoxins. In this study, the influence of
bile acids on
IL-6 signal transduction was analyzed. It was shown that hydrophobic
bile acids such as
glycochenodeoxycholate (GCDC) inhibited IL-6-induced
tyrosine phosphorylation of signal transducer and activator of transcription (STAT) 3 in hepatocytes and in perfused rat liver. This inhibition was accompanied by GCDC-mediated downregulation of
glycoprotein (
gp) 130 expression, whereas gp130 and suppressor of
cytokine signaling 3
messenger RNA and gp80
protein levels remained unaffected. The GCDC-induced downregulation of gp130
protein expression was insensitive to inhibition of proteasomal or lysosomal protein degradation but turned out to be sensitive to inhibition of
caspase-3 or
caspase-8 activity. Accordingly, treatment of
cell extracts with active recombinant
caspase-3 led to a decay of immunoreactive gp130. Moreover, activation of
caspases by
CD95 ligand or hyperosmotic stress also resulted in a downregulation of gp130 levels. This indicates that
caspase activation antagonizes
IL-6 signaling by decay of gp130 levels. However,
caspase inhibition did not prevent GCDC-dependent inhibition of IL-6-induced STAT3 activation, which turned out to be at least partially sensitive to suppression of
p38(MAPK) activation. In conclusion, hydrophobic
bile acids compromise
IL-6 signaling through both a
caspase-mediated downregulation of gp130 and a p38(MAPK)-dependent inhibition of STAT3 phosphorylation. This may contribute to
bile acid-induced hepatotoxicity in
cholestasis through counteracting the known hepatoprotective effects of
IL-6.