Opposing roles for NF-κB/Rel factors p65 and c-Rel in the modulation of neuron survival elicited by glutamate and interleukin-1β

Abstract

The nuclear transcription factors NF-κB/Rel have been shown to function as key regulators of either cell death or survival in neuronal cells. Here, we investigated whether selective activation of diverse NF-κB/Rel family members might lead to distinct effects on neuron viability. In both cultured rat cerebellar granule cells and mouse hippocampal slices, we examined NF-κB/Rel activation induced by two opposing modulators of cell viability: 1) interleukin-1β (IL-1β), which promotes neuron survival and 2) glutamate, which can elicit toxicity. IL-1β produced a prolonged stimulation of NF-κB/Rel factors by inducing both IκBα and IκBβ degradation. Glutamate produced a delayed and transient activation of NF-κB/Rel, which was associated with a brief loss of IκBα. Moreover, IL-1β activated the p50, p65, and c-Rel subunits of NF-κB/Rel, whereas glutamate activated only the p50 and p65 proteins. The inhibition of NF-κB/Rel protein expression by antisense oligonucleotides in cerebellar granule cells showed that p65 was involved in glutamate-mediated cell death, whereas c-Rel was essential for IL-1β-preserved cell survival. Furthermore, the depletion of c-Rel in cultured neurons as well as in the hippocampus from the c-Rel-/- mouse converted the IL-1β effect into toxicity. These findings suggest that, within a single neuron, the balance between cell death and survival in response to external stimuli may rely on the activation of distinct NF-κB/Rel proteins.