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

✍ Scribed by Ronit Haviv; Reuven Stein

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 153 KB
• Volume: 55
• Category: Article
• ISSN: 0360-4012
• DOI: 10.1002/(sici)1097-4547(19990201)55:3<269::aid-jnr1>3.0.co;2-3

✦ Synopsis

Tumor necrosis factor-␣ (TNF␣) 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␣ 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␣ 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␣ induces apoptosis in both naive and primed PC12 cells. The TNF␣-induced apoptosis was inhibited by nerve growth factor (NGF) but not by insulin. These findings suggest that the apoptotic effect of TNF␣ can be inhibited by trophic factors and that the survivalpromoting effect of NGF is mediated by a specific pathway not shared by all tyrosine kinase receptors. The effect of Bcl-2 on TNF␣-induced apoptosis was examined in PC12 cells overexpressing Bcl-2. These cells were resistant to TNF␣-induced apoptosis, suggesting that the apoptotic effect of TNF␣ in PC12 cells is mediated via a pathway controlled by Bcl-2. Examination of the role of caspase-3 like activity in TNF␣-induced apoptosis showed that caspase-3-like proteases are activated, and their substrate, poly (ADP-ribose) polymerase, is cleaved following TNF␣ treatment. In addition, the broad-spectrum inhibitor of caspases, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK), was found to inhibit the TNF␣induced apoptosis of PC12 cells. These results suggest that caspases are activated following TNF␣ treatment and are needed for TNF␣-induced apoptosis in PC12 cells.