TY - JOUR
T1 - TNF-α preconditioning protects neurons via neuron-specific up-regulation of CREB-binding protein
AU - Saha, Ramendra N.
AU - Ghosh, Anamitra
AU - Palencia, Carlos A.
AU - Fung, Yiu K.
AU - Dudek, Serena M.
AU - Pahan, Kalipada
PY - 2009/8/1
Y1 - 2009/8/1
N2 - Despite being a proinflammatory cytokine, TNF-α preconditions neurons against various toxic insults. However, underlying molecular mechanisms are poorly understood. The present study identifies the importance of CREB-binding protein (CBP) in facilitating TNF-α-mediated preconditioning in neurons. Treatment of rat primary neurons with fibrillar amyloid β1-42 (Aβ) resulted in the loss of CBP protein. However, this loss was compensated by TNF-α reconditioning as the expression of neuronal CBP was up-regulated in response to TNF-α treatment. The induction of CBP by TNF-α was observed only in neurons, but not in astroglia and microglia, and it was contingent on the activation of transcription factor NF-κB. Interestingly, antisense knockdown of CBP abrogated the TNF-α-mediated preconditioning of neurons against Aβ and glutamate toxicity. Similarly in vivo, preadministration of TNF-α in mouse neocortex prevented Aβ-induced apoptosis and loss of choline acetyltransferase-positive cholinergic neurons. However, coadministration of cbp antisense, but not scrambled oligonucleotides, negated the protective effect of TNF-α gainst Aβ neurotoxicity. This study illustrates a novel biological role of TNF-α in increasing neuron-specific expression of CBP for preconditioning that may have therapeutic potential against neurodegenerative disorders.
AB - Despite being a proinflammatory cytokine, TNF-α preconditions neurons against various toxic insults. However, underlying molecular mechanisms are poorly understood. The present study identifies the importance of CREB-binding protein (CBP) in facilitating TNF-α-mediated preconditioning in neurons. Treatment of rat primary neurons with fibrillar amyloid β1-42 (Aβ) resulted in the loss of CBP protein. However, this loss was compensated by TNF-α reconditioning as the expression of neuronal CBP was up-regulated in response to TNF-α treatment. The induction of CBP by TNF-α was observed only in neurons, but not in astroglia and microglia, and it was contingent on the activation of transcription factor NF-κB. Interestingly, antisense knockdown of CBP abrogated the TNF-α-mediated preconditioning of neurons against Aβ and glutamate toxicity. Similarly in vivo, preadministration of TNF-α in mouse neocortex prevented Aβ-induced apoptosis and loss of choline acetyltransferase-positive cholinergic neurons. However, coadministration of cbp antisense, but not scrambled oligonucleotides, negated the protective effect of TNF-α gainst Aβ neurotoxicity. This study illustrates a novel biological role of TNF-α in increasing neuron-specific expression of CBP for preconditioning that may have therapeutic potential against neurodegenerative disorders.
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U2 - 10.4049/jimmunol.0801892
DO - 10.4049/jimmunol.0801892
M3 - Article
C2 - 19596989
AN - SCOPUS:68149173324
SN - 0022-1767
VL - 183
SP - 2068
EP - 2078
JO - Journal of Immunology
JF - Journal of Immunology
IS - 3
ER -