Neuronal death in cytokine-activated primary human brain cell culture: role of tumor necrosis factor-α

✍ Scribed by Martha Downen; Terry D. Amaral; Liwei L. Hua; Meng-Liang Zhao; Sunhee C. Lee

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 696 KB
• Volume: 28
• Category: Article
• ISSN: 0894-1491
• DOI: 10.1002/(sici)1098-1136(199911)28:2<114::aid-glia3>3.0.co;2-o

✦ Synopsis

We examined cytokine-mediated neuronal death in neuron-astrocyte cultures from second trimester human fetal cerebrum. In these cultures, high-output inducible nitric oxide synthase (NOS) and tumor necrosis factor-␣ (TNF␣) are expressed in astrocytes after exposure to IL-1␤/IFN␥. Neuronal cell death was evident at Ն48 h following cytokine stimulation. Neutralizing anti-TNF␣ antiserum inhibited (Ϸ48%) neurotoxicity in IL-1␤/IFN␥-treated cultures, demonstrating a role for endogenously produced TNF␣. Interestingly, the degree of neuroprotection conferred by superoxide dismutase or N-methyl D-aspartate (NMDA) receptor antagonists in these cultures was smaller and variable. Similarly, the effect of the NOS inhibitor, N G -monomethyl L-arginine (NMMA) on IL-1␤/IFN␥-induced neuronal death was variable, showing no statistically significant effect when results from more than 30 independent cultures were averaged. Neurons die by apoptosis in cytokine-treated human fetal CNS cultures as shown by the characteristic nuclear morphology as well as positive labeling for TUNEL. Our results demonstrate a potent neurotoxicity mediated by the cytokine combination IL-1␤/IFN␥ in primary human neuron-astrocyte cultures and a crucial role for endogenous TNF␣ in mediating neurotoxicity in this system. These results firmly establish the neurotoxic potential of the inflammatory cytokines IL-1␤ and TNF␣ in the human CNS.