Tumor Necrosis Factor Alpha-Induced Apoptosis in Human Neuronal Cells: Protection by the Antioxidant \u3ci\u3eN\u3c/i\u3e-Acetylcysteine and the Genes \u3ci\u3ebcl-2\u3c/i\u3e and \u3ci\u3ecrmA\u3c/i\u3e

Abstract

Tumor necrosis factor alpha (TNF-α) is a candidate human immunodeficiency virus type 1-induced neurotoxin that contributes to the pathogenesis of AIDS dementia complex. We report here on the effects of exogenous TNF-α on SK-N-MC human neuroblastoma cells differentiated to a neuronal phenotype with retinoic acid. TNF-α caused a dose-dependent loss of viability and a corresponding increase in apoptosis in differentiated SK-N-MC cells but not in undifferentiated cultures. Importantly, intracellular signalling via TNF receptors, as measured by activation of the transcription factor NF-kB, was unaltered by retinoic acid treatment. Finally, overexpression of bcl-2 or crmA conferred resistance to apoptosis mediated by TNF-α, as did the addition of the antioxidant N-acetylcysteine. These results suggest that TNF-a induces apoptosis in neuronal cells by a pathway that involves formation of reactive oxygen intermediates and which can be blocked by specific genetic interventions