Induction of nitric oxide synthase and nitric oxide-mediated apoptosis in neuronal PC12 cells after stimulation with tumor necrosis factor-alpha/lipopolysaccharide.
Exposure of neuronal PC12 cells, differentiated by nerve growth factor, to tumor necrosis factor-alpha (TNF-alpha) and bacterial lipopolysaccharide (LPS) resulted in de novo synthesis of inducible nitric oxide synthase (iNOS) mRNA and protein with an increase up to 24 h. Brain NOS expression was unaffected. The induction of iNOS in differentiated PC12 cells was associated with cell death characterized by features of apoptosis. The NOS inhibitors N-monomethylarginine, aminoguanidine, and 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine.HCl prevented TNF-alpha/LPS-induced cell death and DNA fragmentation, suggesting that the TNF-alpha/LPS-induced cell death is mediated by iNOS-derived NO. This hypothesis is supported by the finding that addition of L-arginine, which serves as a precursor and limiting factor of enzyme-derived NO production, potentiated TNF-alpha/LPS-induced loss of viability.
Heneka
M T
MT
Department of Neurology, University of Tübingen, Germany.
Löschmann
P A
PA
Gleichmann
M
M
Weller
M
M
Schulz
J B
JB
Wüllner
U
U
Klockgether
T
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001120:Arginine / Q000494:pharmacology; D001710:Biotin; D002454:Cell Differentiation / Q000502:physiology; D053938:DNA Fragmentation; D003856:Deoxyuracil Nucleotides; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006146:Guanidines / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D016716:PC12 Cells; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D013194:Staining and Labeling; D013843:Thiazines / Q000494:pharmacology; D014158:Transcription, Genetic / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
C093124:2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine; D003856:Deoxyuracil Nucleotides; D004791:Enzyme Inhibitors; D006146:Guanidines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D013843:Thiazines; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001710:Biotin; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C004479:pimagedine