Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Costelli, P. et al.

Costelli, Aoki, Zingaro, Carbó, Reffo, Lopez-Soriano, Bonelli, Argilés, Baccino,

Mice lacking TNFalpha receptors 1 and 2 are resistant to death and fulminant liver injury induced by agonistic anti-Fas antibody.

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-kappaB 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 TNFalpha-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.[1]

References

Mice lacking TNFalpha receptors 1 and 2 are resistant to death and fulminant liver injury induced by agonistic anti-Fas antibody. Costelli, P., Aoki, P., Zingaro, B., Carbó, N., Reffo, P., Lopez-Soriano, F.J., Bonelli, G., Argilés, J.M., Baccino, F.M. Cell Death Differ. (2003) [Pubmed]

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