Opposing roles for NF-kappa B/Rel factors p65 and c-Rel in the modulation of neuron survival elicited by glutamate and interleukin-1beta.
The nuclear transcription factors NF-kappaB/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-kappaB/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-kappaB/Rel activation induced by two opposing modulators of cell viability: 1) interleukin-1beta (IL-1beta), which promotes neuron survival and 2) glutamate, which can elicit toxicity. IL-1beta produced a prolonged stimulation of NF-kappaB/Rel factors by inducing both IkappaBalpha and IkappaBbeta degradation. Glutamate produced a delayed and transient activation of NF-kappaB/Rel, which was associated with a brief loss of IkappaBalpha. Moreover, IL-1beta activated the p50, p65, and c-Rel subunits of NF-kappaB/Rel, whereas glutamate activated only the p50 and p65 proteins. The inhibition of NF-kappaB/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-1beta-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-1beta 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-kappaB/Rel proteins.
Pizzi
Marina
M
Division of Pharmacology and Experimental Therapeutics, Department of Biomedical Sciences and Biotechnologies, School of Medicine, University of Brescia, 25123 Brescia, Italy. pizzi@med.unibs.it
Goffi
Francesca
F
Boroni
Flora
F
Benarese
Marina
M
Perkins
Scott E
SE
Liou
Hsiou-Chi
HC
Spano
PierFranco
P
D000818:Animals; D001483:Base Sequence; D002470:Cell Survival / Q000187:drug effects* / Q000502:physiology; D003594:Cytoplasmic Granules / Q000378:metabolism; D017931:DNA Primers; D018698:Glutamic Acid / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D017931:DNA Primers; D007375:Interleukin-1; D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel; D018698:Glutamic Acid