Nerve growth factor inhibits apoptosis induced by tumor necrosis factor in PC12 cells.
Tumor necrosis factor-alpha (TNFalpha) may play a role in at least some of the neuronal death that occurs following brain insults or in neurodegenerative diseases. It is therefore important to characterize the mechanism underlying apoptosis induced by TNFalpha in neuronal cells and to identify factors capable of protecting neurons from this death. In the present study, we characterized the apoptotic effect of TNFalpha in PC12 cells, a model system commonly used for studying neuronal apoptosis, and examined the role of Bcl-2 and caspases in this process. We show that TNFalpha induces apoptosis in both naive and primed PC12 cells. The TNFalpha-induced apoptosis was inhibited by nerve growth factor (NGF) but not by insulin. These findings suggest that the apoptotic effect of TNFalpha can be inhibited by trophic factors and that the survival-promoting effect of NGF is mediated by a specific pathway not shared by all tyrosine kinase receptors. The effect of Bcl-2 on TNFalpha-induced apoptosis was examined in PC12 cells overexpressing Bcl-2. These cells were resistant to TNFalpha-induced apoptosis, suggesting that the apoptotic effect of TNFalpha in PC12 cells is mediated via a pathway controlled by Bcl-2. Examination of the role of caspase-3 like activity in TNFalpha-induced apoptosis showed that caspase-3-like proteases are activated, and their substrate, poly (ADP-ribose) polymerase, is cleaved following TNFalpha treatment. In addition, the broad-spectrum inhibitor of caspases, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK), was found to inhibit the TNFalpha-induced apoptosis of PC12 cells. These results suggest that caspases are activated following TNFalpha treatment and are needed for TNFalpha-induced apoptosis in PC12 cells.
Haviv
R
R
Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Ramat Aviv, Israel.
Stein
R
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016716:PC12 Cells / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D007328:Insulin; D009414:Nerve Growth Factors; D014409:Tumor Necrosis Factor-alpha