Abstract
We report induction of TNF-alpha via the calcium/calcineurin/NFAT pathway in PC12 neural cells. In PC12, expression of TNF-alpha mRNA, protein and TNF-alpha gene promoter activity was induced by co-stimulation with phorbol ester and either calcium ionophore A23187 or the L-type Voltage Gated Calcium Channel agonist Bay K 8644. Pre-treatment with calcineurin inhibitors CsA or FK506 inhibited the dominant calcium-dependent component of this induction, limiting it to the level achieved with phorbol ester alone. Promoter activation by Bay was abolished by nifedipine, a specific inhibitor of L-type Voltage Gated Calcium Channels. Exogenous NFAT protein transactivated the TNF-alpha promoter, and the peptide VIVIT-a specific inhibitor of calcineurin/NFAT binding-blocked calcium-inducible transactivation of the TNF-alpha promoter. Given proposed functions of TNF-alpha in spatial learning, memory and the pathogenesis of neurodegenerative diseases, the data presented suggest an important role for calcineurin/NFAT signaling in these key neurological processes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / pharmacology
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Animals
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Calcimycin / pharmacology
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Calcineurin / metabolism*
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Calcium / metabolism*
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Calcium Channel Agonists / pharmacology
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Calcium Signaling / physiology
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Cycloheximide / pharmacology
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Cyclosporine / pharmacology
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation
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Humans
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Immunosuppressive Agents / pharmacology
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Ionophores / pharmacology
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NFATC Transcription Factors / metabolism*
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Neurons* / drug effects
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Neurons* / metabolism
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Oligopeptides / metabolism
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PC12 Cells
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Protein Synthesis Inhibitors / pharmacology
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Rats
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Tacrolimus / pharmacology
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Tetradecanoylphorbol Acetate / pharmacology
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Transcription, Genetic
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism*
Substances
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Calcium Channel Agonists
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Enzyme Inhibitors
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Immunosuppressive Agents
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Ionophores
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NFATC Transcription Factors
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Oligopeptides
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Protein Synthesis Inhibitors
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Tumor Necrosis Factor-alpha
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VIVIT peptide
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Calcimycin
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3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
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Cyclosporine
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Cycloheximide
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Calcineurin
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Tetradecanoylphorbol Acetate
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Calcium
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Tacrolimus