Sustained JNK activation in response to tumor necrosis factor is mediated by caspases in a cell type-specific manner.
In most cell types, tumor necrosis factor (TNF) induces a transient activation of the JNK pathway. However, in NFkappaB-inhibited cells, TNF stimulates also a second sustained phase of JNK activation, which has been implicated in cell death induction. In the present study, we have analyzed the relationship of cell death induction, caspase activity, JNK, and NFkappaB stimulation in the context of TNF signaling in four different cellular systems. In all cases, NFkappaB inhibition enhanced TNF-induced cell death and primed most, but not all, cells for sustained JNK activation. The caspase inhibitor Benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone (Z-VAD-fmk) and overexpression of the antiapoptotic proteins FLIP-L and Bcl2 differentially blocked transient and sustained JNK activation in NFkappaB-inhibited KB and HaCaT cells, indicating that the two phases of TNF-induced JNK activation occur at least in these cellular models by different pathways. Although the broad range caspase inhibitor Z-VAD-fmk and the antioxidant butylated hydroxyanisole interfered with TNF-induced cell death to a varying extent in a cell type-specific manner, inhibition of JNK signaling had no or only a very moderate effect. Notably, the JNK inhibitory effect of neither Z-VAD-fmk nor butylated hydroxyanisole was strictly correlated with the capability of these compounds to rescue cells from TNF-induced cell death. Thus, sustained JNK activation by TNF has no obligate role in TNF-induced cell death and is mediated by caspases and reactive oxygen species in a cell type-specific manner.
Wicovsky
Andreas
A
Department of Molecular Internal Medicine, Medical Clinic and Polyclinic II, University of Würzburg, Röntgenring 11, 97070 Würzburg, Germany.
Müller
Nicole
N
Daryab
Neda
N
Marienfeld
Ralf
R
Kneitz
Christian
C
Kavuri
Shyam
S
Leverkus
Martin
M
Baumann
Bernd
B
Wajant
Harald
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D020169:Caspases / Q000502:physiology*; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology; D009928:Organ Specificity; D017382:Reactive Oxygen Species; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013045:Species Specificity; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000502:physiology
D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D048670:MAP Kinase Kinase 4; D020169:Caspases