TUMOR-NECROSIS-FACTOR ALPHA-INDUCED APOPTOSIS IN HUMAN NEURONAL CELLS- PROTECTION BY THE ANTIOXIDANT N-ACETYLCYSTEINE AND THE GENES BCL-2 AND CRMA

Tumor necrosis factor alpha (TNF-alpha) is a candidate human immunodef iciency virus type 1-induced neurotoxin that contributes to the pathog enesis of AIDS dementia complex. We report here on the effects of exog enous TNF-alpha on SK-N-MC human neuroblastoma cells differentiated to a neuronal phenotype with retinoic acid. TNF-alpha caused a dose-depe ndent loss of viability and a corresponding increase in apoptosis in d ifferentiated SK-N-MC cells but not in undifferentiated cultures. Impo rtantly, intracellular signalling via TNF receptors, as measured by ac tivation of the transcription factor NF-kappa B, was unaltered by reti noic acid treatment. Finally, overexpression of bcl-2 or crmA conferre d resistance to apoptosis mediated by TNF-alpha, as did the addition o f the antioxidant N-acetylcysteine, These results suggest that TNF-alp ha induces apoptosis in neuronal cells by a pathway that involves form ation of reactive oxygen intermediates and which can be blocked by spe cific genetic interventions.