Downen M, Amaral TD, Hua LL, Zhao ML, Lee SC.
Glia 28(2) :114-27, 1999.
Abstract
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-alpha (TNFalpha) are expressed in astrocytes after exposure to IL-1beta/IFNgamma. Neuronal cell death was evident at >/=48 h following cytokine stimulation. Neutralizing anti-TNFalpha antiserum inhibited ( approximately 48%) neurotoxicity in IL-1beta/IFNgamma-treated cultures, demonstrating a role for endogenously produced TNFalpha. 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-1beta/IFNgamma-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-1beta/IFNgamma in primary human neuron-astrocyte cultures and a crucial role for endogenous TNFalpha in mediating neurotoxicity in this system. These results firmly establish the neurotoxic potential of the inflammatory cytokines IL-1beta and TNFalpha in the human CNS. Copyright 1999 Wiley-Liss, Inc.
Important Points:
-Model: human neuron-astrocyte culture
-treatment with IL-1B/IFNgamma caused TNF-alpha expression and neuronal death at 48h or longer
-neural death is apoptotic
-neurotoxicity could be attenuated by TNF-a antiserum
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