The neurotrophic factors, nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF), are produced by astrocytes, and are induced by inflammatory stimuli including bacterial lipopolysaccharide and pro-inflammatory cytokines. In this study, we examined the regulatory mechanisms of tumor necrosis factor-α (TNF-α)-induced production of neurotrophic factors. We show here that cultured astrocytes express both TNF-α receptor 1 (TNFR1) and TNFR2, and that activation of these receptors by TNF-α promotes expression of both NGF and GDNF. In addition, we observe that not only exogenous TNF-α but also TNF-α produced by astrocytes induce NGF and GDNF production in astrocytes. These results suggest that an autocrine loop involving TNF-α contributes to the production of neurotrophic factors in response to inflammation.