Prevention of nuclear localization of activated caspases correlates with inhibition of apoptosis.
The caspase family proteases are principal components of the apoptotic pathway. In this study we demonstrate that caspase-1-like proteases and interleukin-1 beta are important for death induced by various stimuli in cell lines, primary fibroblasts and primary sensory neurons. Furthermore, we show by immunohistochemistry that during the cell death process endogenous caspase-1-like proteases translocate into the nucleus. This translocation is stimulated by interleukin-1 receptor activation. Translocation of caspase-1-like proteases and cell death can be partially prevented by blocking the interleukin-1 receptor with the interleukin-1 receptor antagonist. This finding offers for the first time a mechanistic explanation for the protective effect of the interleukin-1 receptor antagonist against cell death. Furthermore, our data suggest that caspase-1-like proteases have a function in the nucleus which is necessary for completion of the cell death program. In cultured DRG neurons from embryonic mice the combined inhibition of caspases and the interleukin-1 receptor have an additive effect and fully prevent semaphorin III-induced neuronal death. This shows that endogenous caspases work together with IL-1 beta in Semaphorin III-induced neuronal death. We hypothesize that the cell death process involves a double activation step, probably including an interleukin-1 autocrine loop. This model can explain our finding that combined inhibition of caspases and interleukin-1 receptor is necessary to strongly inhibit the cell death process.
Brain Research Institute, Department of Neuromorphology, University of Zurich, ETH Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
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Fankhauser
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Friedlander
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Gagliardini
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D002458:Cell Fractionation; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D005347:Fibroblasts; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011233:Precipitin Tests; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D040121:Semaphorin-3A; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D002352:Carrier Proteins; D007375:Interleukin-1; D009419:Nerve Tissue Proteins; D017472:Receptors, Interleukin-1; D011993:Recombinant Fusion Proteins; C108639:SEMA3A protein, human; C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases