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  • Title: Taurolithocholic acid-3 sulfate induces CD95 trafficking and apoptosis in a c-Jun N-terminal kinase-dependent manner.
    Author: Graf D, Kurz AK, Fischer R, Reinehr R, Häussinger D.
    Journal: Gastroenterology; 2002 May; 122(5):1411-27. PubMed ID: 11984527.
    Abstract:
    BACKGROUND & AIMS: 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.
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