Downen M. Amaral TD. Hua LL. Zhao ML. Lee SC.
Neuronal death in cytokine-activated primary human brain cell
culture: role of tumor necrosis factor-alpha. GLIA.
28(2):114-27, 1999 Nov
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-1betagamma. 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.
Important Points:
-Model: neuron/astrocyte culture, human fetal
-time course of neural death via Il1 B plus IFN gamma: 1.4X (24h), 7.6X (3d), 11.8X (5d)
-death is apoptotic (TUNEL), and not NMDA-dependent
-Il1 B plus IFN gamma-mediated neural death is attenuated by TNF-alpha (48% max.), but TNF-a alone is toxic: this depends on the receptor-signalling cascade activated
-the concentration of TNF-a required for protective effects (approx. 100ng) is higher than that maximally released in culture by IL1/IFN treatment (high picogram to low nanogram)
-cytokine action is extremely context dependent: 1 cytokine can have different effects depending on the target cells, factors in the microenvironment, whether acting alone or in combination with other cytokines
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