Taurolithocholic acid-3 sulfate induces CD95 trafficking and apoptosis in a c-Jun N-terminal kinase-dependent manner.
OBJECTIVE
Prevention of bile acid-induced apoptosis is of therapeutic interest and requires the understanding of underlying mechanisms.


METHODS
The effect of tauroursodeoxycholate (TUDC) on taurolithocholic acid-3 sulfate (TLCS)-induced apoptosis was studied in cultured rat hepatocytes.


RESULTS
TLCS induced activation of caspases 8, 9, and 3 and hepatocyte apoptosis. These effects were abolished by TUDC in a PI 3-kinase-/protein kinase B (PKB)-, p38(MAPK)-, and extracellular signal-regulated kinase-2 (Erk-2)-independent manner. These protein kinases were activated by both TLCS and TUDC, however, with different kinetics. TLCS, but not TUDC, led to a sustained activation of c-Jun N-terminal kinase (JNK) and CD95 trafficking to the plasma membrane; both TLCS effects were prevented by TUDC. Inhibition of JNK1 or protein kinase C prevented TLCS-induced CD95 membrane trafficking and blunted the apoptotic response. The apoptotic potency of other bile acids paralleled their ability to induce sustained JNK activation.


CONCLUSIONS
Protection by TUDC against TLCS-induced apoptosis starts upstream of caspase 8 activation and is independent of a PI 3-kinase-dependent survival pathway. JNK activation may be important for bile acid-induced apoptosis by triggering ligand-independent CD95 surface trafficking and activation of apoptosis.
Graf
Dirk
D
Department of Gastroenterology, Hepatology and Infectiology, Medizinische Einrichtungen der Heinrich-Heine Universität Düsseldorf, Germany.
Kurz
Anna Kordelia
AK
Fischer
Richard
R
Reinehr
Roland
R
Häussinger
Dieter
D
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000502:physiology; D002478:Cells, Cultured; D022781:Hepatocytes / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D013657:Taurodeoxycholic Acid / Q000494:pharmacology; D013658:Taurolithocholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019014:fas Receptor / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D013657:Taurodeoxycholic Acid; D013658:Taurolithocholic Acid; D019014:fas Receptor; D048051:p38 Mitogen-Activated Protein Kinases; C066776:taurolithocholic acid 3-sulfate; C505528:Casp8 protein, rat; C506435:Casp9 protein, rat