Inhibition of p75 tumor necrosis factor receptor by antisense oligonucleotides increases hypoxic injury and beta-amyloid toxicity in human neuronal cell line.
Recent evidence indicates that tumor necrosis factor-alpha (TNF-alpha) is up-regulated following brain injury and in neurodegenerative disorders such as stroke, multiple sclerosis, Parkinson's disease, and Alzheimer's disease. TNF-alpha elicits its biological effects through two distinct TNF receptor (TNFR) subtypes: p55 TNFR (TNFR1) and p75 TNFR (TNFR2). Studies have demonstrated that the p55 TNFR contributes to cell death, whereas the role of the p75 TNFR in neuronal viability is unclear. To better understand the role of p75 TNFR, we treated human neuronal SH-SY5Y cells with phosphorothioate-modified antisense oligonucleotides (ASO) for p75 TNFR and established that ASO inhibited p75 TNFR expression. Treatment of SH-SY5Y cells with ASO alone did not affect cell viability, whereas treatment with both ASO and human TNF-alpha significantly increased cell death relative to treatment with TNF-alpha alone. Moreover, addition of ASO significantly increased the level of cell injury observed following hypoxic conditions or exposure of beta-amyloid peptide. These results indicate that inhibition of p75 TNFR using ASO increases the vulnerability of neurotypic cells to insults and suggest that the p75 TNFR may not be required for normal neuronal cell viability but rather plays a protective role following injury.
Shen
Y
Y
Neuroscience Department, Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA. Shen.Yong@igate.abbott.com
Li
R
R
Shiosaki
K
K
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D015703:Antigens, CD / Q000737:chemistry*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D000860:Hypoxia / Q000473:pathology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry*; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D015703:Antigens, CD; D016376:Oligonucleotides, Antisense; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D007770:L-Lactate Dehydrogenase