Up-regulation of BDNF in Astrocytes by TNF-α: A Case for the Neuroprotective Role of Cytokine
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Tumor necrosis factor-alpha (TNF-α) is widely known to be involved in physiological and pathophysiological processes of the brain where this proinflammatory cytokine is implicated with regulation of inflammatory and survival components. We report that TNF-α up-regulates exon-IV-bdnf mRNA and brain-derived neurotrophic factor (BDNF) protein in primary astrocytes. The BDNF protein was detectable both in cellular lysate and in the extracellular medium. Activation of NF-κB by TNF-α and inhibition of TNF-α-induced BDNF expression by Δp65 (a dominant-negative mutant) and NEMO-binding domain peptide (an inhibitor of NF-κB) suggests that TNF-α induces BDNF expression through the activation of NF-κB. Similarly, TNF-α induced the activation of C/EBPβ and the expression of BDNF was sensitive to overexpression of ΔC/EBPβ (a dominant-negative mutant) and ETO (an inhibitor of C/EBPβ). Among three MAP kinases, TNF-α-induced BDNF up-regulation was sensitive only to inhibitors of ERK MAP kinase. However, the ERK MAP kinase pathway was coupled to activation of C/EBPβ but not NF-κB. Taken together, this study identifies a novel property of TNF-α in inducing the expression of BDNF via NF-κB and C/EBPβ in astrocytes that may be responsible for neurotrophic activity of the cytokine.
Key wordsastrocytes BDNF TNF-α NF-κB C/EBPβ MAP kinase
This study was supported by grants from NIH (NS39940 and NS48923), National Multiple Sclerosis Society (RG3422A1/1), and Michael J. Fox Foundation for Parkinson's research. The authors would like to acknowledge Marian Schmidt of UNMC for her excellent work in animal handling, Dr. Steve O'Rahilly and Dr. Justin Rochford of the University of Cambridge for ETO constructs, and Avik Roy of Pahan Laboratory for his help in the initial stages of this study.
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