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

Abstract

The liver is particularly susceptible to Fas-mediated cytotoxicity. Mice given an adequate parenteral dose of agonistic antiFas 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 À ) 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 wildtype mice (R þ ), 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 À animals. The DNA-binding activity of the NF-jB transcription factor is enhanced after aFas treatment, but much more markedly in R À than in R þ mice. Bcl2, while unchanged in untreated animals, is markedly upregulated in R À but not in R þ 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 TNFa-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.

Minimal hepatic toxicity of Onyx-015: spatial restriction of coxsackie-adenoviral receptor in normal liver

“…[43][44][45][46] In experimental systems, the administration of neutralizing antibodies to TNF has been shown to blunt the impact of inflammation on changes in transaminase levels. 40,42 Hepatic dysfunction due to the induction of high levels of inflammatory cytokines is consistent with the time course of these changes and the requirement for repetitive treatments. While all patients had elevated levels of inflammatory cytokines following treatment with Onyx-015, only one patient had significant increases in AST and ALT levels, suggesting that factors in addition to elevated cytokines levels contribute to the observed transaminitis.…”

“…Transient increases in the levels of unconjugated bilirubin are seen during acute infections and are mediated by cytokines including TNF. [40][41][42][43][44] …”

A Role for cGMP in Inducible Nitric-oxide Synthase (iNOS)-induced Tumor Necrosis Factor (TNF) α-converting Enzyme (TACE/ADAM17) Activation, Translocation, and TNF Receptor 1 (TNFR1) Shedding in Hepatocytes

“…Hepatocytes express large amounts of TNFR1 (17,18), and activation of this receptor by TNF␣ during inflammation can lead to hepatocyte apoptosis (19). However, TNFR1 can also be cleaved from the cell surface through proteolytic ectodomain shedding driven by activation of TNF␣-converting enzyme (TACE/ADAM17).…”

Protective effects of HFE7A, mouse anti-human/mouse Fas monoclonal antibody against acute and lethal hepatic injury induced by Jo2

“…Another mechanism of Fas-associated liver damage and mortality elicited by Jo2 is TNF-a-mediated liver injury. Fas stimulation recruits neutrophils and activates Kupffer cells that secrete TNF-a, which aggravates Fas-mediated liver injury (Cazanave et al 2008;Costelli et al 2003;Mizuhara et al 1994;Matsuki et al 2002). On the other hand, Jodo et al reported that Jo2 delivers a Fas-mediated apoptosis signal to sinusoidal lining cells prior to hepatic parenchymal cells and this apoptosis signal is dependant on FccRII expression on sinusoidal lining cells.…”