Costelli P, Aoki P, Zingaro B, Carbó N, Reffo P, Lopez-Soriano F J, Bonelli G, Argilés J M, Baccino F M
Dipartimento di Medicina e Oncologia Sperimentale, Università di Torino, Italy.
Cell Death Differ. 2003 Sep;10(9):997-1004. doi: 10.1038/sj.cdd.4401281.
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.
肝脏对Fas介导的细胞毒性特别敏感。已知给予足够肠外剂量的激动性抗Fas抗体（aFas）或FasL的小鼠会发生毁灭性的肝损伤，并在数小时内死亡。目前的研究表明，缺乏TNFR1和TNFR2（R(-)）的小鼠单次注射aFas后均能存活，否则会迅速致死，并且与数小时内遭受严重肝损伤的野生型小鼠（R(+)）相比，会发展为轻度肝损伤，最终导致不同家族蛋白酶（半胱天冬酶3、8和9样、钙蛋白酶、组织蛋白酶B）的活性增加。Fas和FasL的总体组织水平以及肝细胞表面的Fas表达在R(-)动物的肝脏中均未改变。aFas处理后，NF-κB转录因子的DNA结合活性增强，但在R(-)小鼠中比在R(+)小鼠中更明显。Bcl2在未处理的动物中未改变，但在接受aFas攻击的R(-)小鼠中显著上调，而在R(+)小鼠中则未上调。正常的TNFR1/TNFR2表型对于小鼠全身和肝脏特异性aFas毒性的充分发挥是必需的，这很可能意味着aFas处理以某种方式导致TNFα-TNFRs系统的激活，并且这种激活与Fas介导的信号协同作用，导致暴发性肝损伤和动物死亡。Fas和TNFRs介导的信号系统在全身和肝脏特异性aFas毒性中的这种相互作用背后的确切细胞和分子细节在很大程度上仍有待阐明。
