Sustained JNK Activation in Response to Tumor Necrosis Factor Is Mediated by Caspases in a Cell

Inmost cell types, tumornecrosis factor (TNF) induces a tran-sient activation of the JNK pathway. However, in NFB-inhib-ited cells, TNF stimulates also a second sustained phase of JNK activation, which has been implicated in cell death induction. In thepresent study,wehave analyzed the relationshipof cell death induction, caspase activity, JNK, and NFB stimulation in the context of TNF signaling in four different cellular systems. In all cases, NFB inhibition enhanced TNF-induced cell death and primedmost, but not all, cells for sustained JNK activation. The caspase inhibitor Benzyloxycarbonyl-Val-Ala-Asp(OMe)-flu-oromethyl ketone (Z-VAD-fmk) and overexpression of the anti-apoptotic proteins FLIP-L and Bcl2 differentially blocked tran-sient and sustained JNK activation in NFB-inhibited KB and HaCaT cells, indicating that the two phases of TNF-induced JNK activation occur at least in these cellular models by differ