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 immunodeficiency virus type 1-induced neurotoxin that contributes to the pathogenesis of AIDS dementia complex. We report here on the effects of exogenous TNF-alpha on SK-N-MC human neuroblastoma cells differentiated to a neuronal phenotype with retinoic acid, TNF-alpha 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-kappa B, was unaltered by retinoic acid treatment. Finally, overexpression of bcl-2 or crmA conferred resistance to apoptosis mediated by TNF-alpha, as did the addition of the antioxidant N-acetylcysteine. These results suggest that TNF-alpha induces apoptosis in neuronal cells by a pathway that involves formation of reactive oxygen intermediates and which can be blocked by specific genetic interventions.
Talley
A K
AK
Department of Neurology (Child Neurology Division), University of Rochester Medical Center, New York 14642, USA.
Dewhurst
S
S
Perry
S W
SW
Dollard
S C
SC
Gummuluru
S
S
Fine
S M
SM
New
D
D
Epstein
L G
LG
Gendelman
H E
HE
Gelbard
H A
HA
D015526:AIDS Dementia Complex / Q000209:etiology; D000111:Acetylcysteine / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D017077:Culture Media, Conditioned; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2; D015843:Serpins / Q000235:genetics / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014764:Viral Proteins
D000975:Antioxidants; D017077:Culture Media, Conditioned; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D015843:Serpins; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D014212:Tretinoin; C074641:interleukin-1beta-converting enzyme inhibitor; D000111:Acetylcysteine