Tumor necrosis factor-alpha (TNF-alpha) 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-alpha 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-kappaB by TNF-alpha and inhibition of TNF-alpha-induced BDNF expression by Deltap65 (a dominant-negative mutant) and NEMO-binding domain peptide (an inhibitor of NF-kappaB) suggests that TNF-alpha induces BDNF expression through the activation of NF-kappaB. Similarly, TNF-alpha induced the activation of C/EBPbeta and the expression of BDNF was sensitive to overexpression of DeltaC/EBPbeta (a dominant-negative mutant) and ETO (an inhibitor of C/EBPbeta). Among three MAP kinases, TNF-alpha-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/EBPbeta but not NF-kappaB. Taken together, this study identifies a novel property of TNF-alpha in inducing the expression of BDNF via NF-kappaB and C/EBPbeta in astrocytes that may be responsible for neurotrophic activity of the cytokine.