Nerve growth factor inhibits apoptosis induced by tumor necrosis factor in PC12 cells

Tumor necrosis factor-alpha (TNF alpha) 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 TNF alpha in neuronal cells and to identify factors capable of protecting neurons from this death, In the present study, we characterized the apoptotic effect of TNF alpha 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 TNF alpha induces apoptosis in both naive and primed PC12 cells, The TNF alpha-induced apoptosis was inhibited by nerve growth factor (NGF) but not by insulin. These findings suggest that the apoptotic effect of TNF alpha 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 TNF alpha-induced apoptosis was examined in PC12 cells overexpressing Bcl-2. These cells were resistant to TNF alpha-induced apoptosis, suggesting that the apoptotic effect of TNF alpha in PC12 cells is mediated via a pathway controlled by Bcl-2, Examination of the role of caspase-3 like activity in TNF alpha-induced apoptosis showed that caspase-3-like proteases are activated, and their substrate, poly (ADP-ribose) polymerase, is cleaved following TNF alpha treatment. In addition, the broad-spectrum inhibitor of caspases, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK), was found to inhibit the TNF alpha-induced apoptosis of PC12 cells. These results suggest that caspases are activated following TNF alpha treatment and are needed for TNFa-induced apoptosis in PC12 cells. J. Neurosci, Res,55:269-277, 1999, (C) 1999 Wiley-Liss, Inc.