Inhibition of taurolithocholate 3-sulfate-induced apoptosis by cyclic AMP in rat hepatocytes involves protein kinase A-dependent and -independent mechanisms

Arch Biochem Biophys. 2003 Jul 1;415(1):34-42. doi: 10.1016/s0003-9861(03)00224-8.

Abstract

The mechanisms underlying the inhibition of bile acid-induced apoptosis by cyclic AMP (cAMP) were studied in 24-h-cultured rat hepatocytes. Taurolithocholate 3-sulfate (TLCS, 100 micromol/l) led to a sustained activation of mitogen activated protein (MAP) kinases (JNK, p38(MAPK), and ERKs), dephosphorylation of protein kinase B (PKB), activation of caspases 3 and 8, and hepatocyte apoptosis. cAMP prevented TLCS-induced apoptosis, shifted the persistent TLCS-induced MAP kinase response to a transient pattern, and prevented PKB dephosphorylation. TLCS-induced CD95 and TRAIL receptor-2 trafficking to the plasma membrane were significantly inhibited. Blockade of protein kinase A (PKA) abolished the inhibitory effect of cAMP on TLCS-induced CD95 membrane targeting, but not TRAIL receptor-2 membrane targeting, PKB and MAP kinase responses. H89, an inhibitor of PKA, had no effect on cAMP-induced inhibition of TLCS-triggered poly(ADP) ribose polymerase (PARP) cleavage and caspase activation, but abolished the cAMP-induced inhibition of TLCS-triggered TUNEL- and Annexin V staining. It is concluded that cAMP inhibits bile acid-induced apoptosis via PKA-dependent and -independent mechanisms.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Bile Acids and Salts / biosynthesis
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases / biosynthesis
  • Caspases / drug effects
  • Cells, Cultured
  • Cyclic AMP / pharmacology*
  • Cyclic AMP-Dependent Protein Kinases
  • Hepatocytes / cytology
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism*
  • Male
  • Mitogen-Activated Protein Kinase Kinases / biosynthesis
  • Mitogen-Activated Protein Kinase Kinases / drug effects
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins / drug effects
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Rats, Wistar
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / biosynthesis
  • Receptors, Tumor Necrosis Factor / drug effects
  • Reference Values
  • Reproducibility of Results
  • Sensitivity and Specificity
  • Taurolithocholic Acid / analogs & derivatives*
  • Taurolithocholic Acid / pharmacology*
  • fas Receptor / metabolism

Substances

  • Bile Acids and Salts
  • Proto-Oncogene Proteins
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf10b protein, rat
  • fas Receptor
  • taurolithocholic acid 3-sulfate
  • Taurolithocholic Acid
  • Cyclic AMP
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Cyclic AMP-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • Casp3 protein, rat
  • Casp8 protein, rat
  • Casp9 protein, rat
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases