TNF-alpha preconditioning protects neurons via neuron-specific up-regulation of CREB-binding protein.
J Immunol
; 183(3): 2068-78, 2009 Aug 01.
Article
en En
| MEDLINE
| ID: mdl-19596989
Despite being a proinflammatory cytokine, TNF-alpha 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-alpha-mediated preconditioning in neurons. Treatment of rat primary neurons with fibrillar amyloid beta1-42 (Abeta) resulted in the loss of CBP protein. However, this loss was compensated by TNF-alpha preconditioning as the expression of neuronal CBP was up-regulated in response to TNF-alpha treatment. The induction of CBP by TNF-alpha was observed only in neurons, but not in astroglia and microglia, and it was contingent on the activation of transcription factor NF-kappaB. Interestingly, antisense knockdown of CBP abrogated the TNF-alpha-mediated preconditioning of neurons against Abeta and glutamate toxicity. Similarly in vivo, preadministration of TNF-alpha in mouse neocortex prevented Abeta-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-alpha against Abeta neurotoxicity. This study illustrates a novel biological role of TNF-alpha in increasing neuron-specific expression of CBP for preconditioning that may have therapeutic potential against neurodegenerative disorders.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Factor de Necrosis Tumoral alfa
/
Fármacos Neuroprotectores
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Proteína de Unión a CREB
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Neuronas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Immunol
Año:
2009
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos