ABSTRACT
In all these situations, cytokines appear to play an important role in neuronal cell death and survival, although the precise mechanisms are still being elucidated. In vitro studies in mixed neuronal/glial cultures show that several cytokines play dual context-dependent maturation roles in either promoting or preventing apoptotic neuronal cell death. For example, IL-la exhibits a dose-related neurotoxic effect in mature fetal dorsal root ganglion cells in culture (8) which can be blocked with neutralizing IL-l antibody. In contrast, in immature neurons in culture, IL-la prevents the naturally occurring apoptotic neuronal cell death that occurs during electrical blockade with tetrodotoxin. Other cytokines that exhibit such dual contextdependent effects on neuronal cell death and survival include TNF-a, which mediates apoptosis through a TNF-a-<:eramide signaling pathway and mediates survival through TNF-a-NFKB signaling pathways (9). In nondepolarizing, low K+ culture conditions, TNF-a, IL-10, and JL-13 all promote survival (10). This dual effect of cytokines expressed within the CNS is similar to the role played by cytokines in the periphery, that of helping to select populations of mature cell types by enhancing survival of some and eliminating others through apoptosis. In immune cells, and similarly in neurons, the transcription factor NFKB may play a pivotal role in these context-dependent effects on cell survival or death, acting much like a switch that when induced can block death signals and when suppressed or blocked can allow death signal activation of apoptotic pathways. Further discussion of these mechanisms will be presented in the second article in this series (11).
