TNF-α preconditioning protects neurons via neuron-specific up-regulation of CREB-binding protein

Despite being a proinflammatory cytokine, TNFpreconditions 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-mediated preconditioning in neurons. Treatment of rat primary neurons with fibrillar amyloid 1–42 (A ) resulted in the loss of CBP protein. However, this loss was compensated by TNFpreconditioning as the expression of neuronal CBP was up-regulated in response to TNFtreatment. The induction of CBP by TNFwas observed only in neurons, but not in astroglia and microglia, and it was contingent on the activation of transcription factor NFB. Interestingly, antisense knockdown of CBP abrogated the TNF-mediated preconditioning of neurons against A and glutamate toxicity. Similarly in vivo, preadministration of TNFin mouse neocortex prevented A -induced apoptosis and loss of choline acetyltransferase-positive cholinergic neurons. However, coadministration of cbp antisense, but not scrambled oligonucleotides, negated the protective effect of TNFagainst A neurotoxicity. This study illustrates a novel biological role of TNFin increasing neuron-specific expression of CBP for preconditioning that may have therapeutic potential against neurodegenerative disorders. The Journal of Immunology, 2009, 183: 2068–2078.