Abstract
The liver is particularly susceptible to Fas-mediated cytotoxicity. Mice given an adequate parenteral dose of agonistic anti-Fas antibody (aFas) or of FasL are known to develop a devastating liver injury and to die in a few hours. The present work shows that mice lacking TNFR1 and TNFR2 (R−) both survive a single dose of aFas, otherwise rapidly lethal, and develop a mild form of hepatic damage, compared to the much more severe liver injury that in a few hours strikes wild-type mice (R+), eventually involving increased activity of proteases of different families (caspase 3-, 8-, and 9-like, calpains, cathepsin B). Neither the overall tissue levels of Fas and FasL nor Fas expression at the hepatocyte surface are altered in the liver of R− animals. The DNA-binding activity of the NF-κB transcription factor is enhanced after aFas treatment, but much more markedly in R− than in R+ mice. Bcl2, while unchanged in untreated animals, is markedly upregulated in R− but not in R+ mice challenged with aFas. The requirement of a normal TNFR1/TNFR2 phenotype for full deployment of the general and liver-specific aFas toxicity in mice most likely implies that treatment with aFas in some way results in activation of the TNFα-TNFRs system and that this activation synergizes with Fas-mediated signals in causing the fulminant liver injury and the animal death. The precise cellular and molecular details underlying this interplay between Fas- and TNFRs-mediated signaling systems in the general and liver-specific aFas toxicity largely remain to be clarified.
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Abbreviations
- aFas:
-
agonistic anti-Fas antibody
- R+:
-
normal mice
- R−:
-
mice knocked out for TNF-R1 and TNF-R2
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Acknowledgements
This work has been supported by the Ministero per l'Istruzione, l'Università e la Ricerca (MIUR, Roma; Italy-Spain Integrated Actions). P Aoki is recipient of a fellowship from the Fundacion Antorchas, Brazil.
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Costelli, P., Aoki, P., Zingaro, B. et al. Mice lacking TNFα receptors 1 and 2 are resistant to death and fulminant liver injury induced by agonistic anti-Fas antibody. Cell Death Differ 10, 997–1004 (2003). https://doi.org/10.1038/sj.cdd.4401281
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DOI: https://doi.org/10.1038/sj.cdd.4401281
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