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.
Costelli
P
P
Dipartimento di Medicina e Oncologia Sperimentale, Università di Torino, Italy. paola.costelli@unito.it
Aoki
P
P
Zingaro
B
B
Carbó
N
N
Reffo
P
P
Lopez-Soriano
F J
FJ
Bonelli
G
G
Argilés
J M
JM
Baccino
F M
FM
D000818:Animals; D000906:Antibodies / Q000633:toxicity; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis; D053222:Fas Ligand Protein; D006520:Hepatitis, Animal / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000473:pathology / Q000648:ultrastructure; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D015703:Antigens, CD; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor