ICE-protease inhibitors block murine liver injury and apoptosis caused by CD95 or by TNF-α

doi:10.1016/S0165-2478(96)02642-9

Immunology Letters

Volume 55, Issue 1, January 1997, Pages 5-10

https://doi.org/10.1016/S0165-2478(96)02642-9 Get rights and content

Abstract

The two apoptosis receptors of mammalian cells, i.e. the 55 kDa TNF receptor (TNF-R1) and CD95 (Fas/APO1) are activated independently of each other, however, their signaling involves a variety of ICE-related proteases [1]. We used a cell-permeable inhibitor of ICE-like protease activity to examine in vivo whether post-receptor signaling of TNF and CD95 are fully independent processes. Mice pretreated with the inhibitor, Z-VAD-fluoromethylketone (FMK) were dose-dependently protected from liver injury caused by CD95 activation as determined by plasma alanine aminotransferase and also from hepatocyte apoptosis assessed by DNA fragmentation (ID₅₀=0.1 mg/kg). A dose of 10 mg/kg protected mice also from liver injury induced by TNF-α. Similar results were found when apoptosis was initiated via TNF-α or via CD95 in primary murine hepatocytes (IC₅₀=1.5 nM) or in various human cell lines. In addition to prevention, an arrest of cell death by Z-VAD-FMK was demonstrated in vivo and in vitro after stimulation of apoptosis receptors. These findings show in vitro and in vivo in mammals that CD95 and the TNF-α receptor share a distal proteolytic apoptosis signal.

References (28)

E. Mita et al.
Biochem. Biophys. Res. Commun.
(1994)
M. Tewari et al.
J. Biol. Chem.
(1995)
J. Yuan et al.
Cell
(1993)
M. Miura et al.
Cell
(1993)
J. Kamens et al.
J. Biol. Chem.
(1995)
L. Wang et al.
Cell
(1994)
J. Glanz
Science
(1996)
N. Hiramatsu et al.
Hepatology
(1994)
P.R. Galle et al.
J. Exp. Med.
(1995)
S.M. Krams et al.
Transplantation
(1995)

V. Lehmann et al.

J. Exp. Med.

(1987)

G. Tiegs et al.

Biochem. Pharmacol.

(1989)

M. Leist et al.

J. Immunol.

(1994)

M. Leist et al.

Am. J. Pathol.

(1995)

Cited by (121)

Pirfenidone attenuates acetaminophen-induced liver injury via suppressing c-Jun N-terminal kinase phosphorylation
2022, Toxicology and Applied Pharmacology
Acetaminophen (APAP)-induced liver injury is the most frequent cause of acute liver failure in Western countries. Pirfenidone (PFD), an orally bioavailable pyridone derivative, is clinically used for idiopathic pulmonary fibrosis treatment and has antifibrotic, anti-inflammatory, and antioxidant effects. Here we examined the PFD effect on APAP-induced liver injury.
In a murine model, APAP caused serum alanine aminotransferase elevation attenuated by PFD treatment. We performed terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) and vital propidium iodide (PI) stainings simultaneously. APAP induced TUNEL-positive/PI-negative necrosis around the central vein and subsequent TUNEL-negative/PI-positive oncotic necrosis with hemorrhage and caused the upregulation of hypercoagulation- and hypoxia-associated gene expressions. PFD treatment suppressed these findings. Western blotting revealed PFD suppressed APAP-induced c-Jun N-terminal kinase (JNK) phosphorylation despite no effect on JNK phosphatase expressions.
In conclusion, simultaneous TUNEL and vital PI staining is useful for discriminating APAP-induced necrosis from typical oncotic necrosis. Our results indicated that PFD attenuated APAP-induced liver injury by suppressing TUNEL-positive necrosis by directly blocking JNK phosphorylation. PFD is promising as a new option to prevent APAP-induced liver injury.
Experimental models of hepatotoxicity related to acute liver failure
2016, Toxicology and Applied Pharmacology
Citation Excerpt :
In addition, contact between neutrophils and target cells seems not to be required for cell injury in vitro compared to the in vivo situation, as conditioned medium of activated neutrophils is as effective in killing hepatocytes as the neutrophils themselves (Ho et al., 1996). Cell death in the Gal/ET model is also caused by TNFα-induced apoptosis involving the TNF receptor 1 (Leist et al., 1995) and caspase activation (Fig. 4) (Jaeschke et al., 1998; Künstle et al., 1997). The default signaling of the TNF receptor is activation of nuclear factor kappa beta resulting in the induction of pro-inflammatory and anti-apoptotic genes (Liedtke and Trautwein, 2012).
Acute liver failure can be the consequence of various etiologies, with most cases arising from drug-induced hepatotoxicity in Western countries. Despite advances in this field, the management of acute liver failure continues to be one of the most challenging problems in clinical medicine. The availability of adequate experimental models is of crucial importance to provide a better understanding of this condition and to allow identification of novel drug targets, testing the efficacy of new therapeutic interventions and acting as models for assessing mechanisms of toxicity. Experimental models of hepatotoxicity related to acute liver failure rely on surgical procedures, chemical exposure or viral infection. Each of these models has a number of strengths and weaknesses. This paper specifically reviews commonly used chemical in vivo and in vitro models of hepatotoxicity associated with acute liver failure.
Involvement of the proteasome and caspase activation in hippocampal long-term depression induced by the serine protease subtilisin
2013, Neuroscience
The serine protease subtilisin-A produces a long-term depression (LTD) of synaptic potentials in hippocampal slices which differs mechanistically from classical LTD. Since caspases have been implicated in hippocampal plasticity, this study examined a possible role for these enzymes in subtilisin-induced LTD. Subtilisin produced a concentration-dependent decrease in the size of field excitatory synaptic potentials (fEPSPs), which was not prevented or modified by the caspase inhibitors Z-VAD(OMe)-fmk and Z-DEVD-fmk. Similarly Z-VAD(OMe)-fmk did not modify the selective loss of protein expression produced by subtilisin. Subtilisin reduced the expression of procaspase-3 and caspase-9 but, while caspase-9 was converted to its conventionally activated form (39 kDa), caspase-3 was metabolised along a non-canonical pathway to a 29/30 kDa protein rather than the classical 17/19 kDa fragments. Both Z-VAD(OMe)-fmk and Z-DEVD-fmk were unable to prevent the reduced expression of Postsynaptic Density Protein-95, Vesicle-Associated Membrane Protein-1 and Unco-ordinated 5H3 proteins produced by subtilisin, although MG132 did produce partial recovery from subtilisin-induced depression of fEPSPs. When tested on long-term potentiation (LTP) induced by theta stimulation in the stratum radiatum, MG132 inhibited the immediate increase in fEPSP size but generated a higher plateau LTP. Twin LTP stimulation generated a further increase in LTP amplitude in control slices but not in slices exposed to MG132. The results indicate that subtilisin does produce caspase activation but that this does not contribute to its induction of LTD. However, activation of the proteasome does contribute to subtilisin-induced LTD and may also play a modulatory role in electrically induced LTP.
Protective Roles for Caspase-8 and cFLIP in Adult Homeostasis
2013, Cell Reports
Citation Excerpt :
This is in agreement with the finding that liver-specific ablation of caspase-8 has no pathological effect (Kang et al., 2004). Moreover, neither tumor necrosis factor (TNF) nor anti-CD95, in combination with the pan-caspase inhibitor zVAD-fmk, induces liver necrosis (Chandler et al., 1998; Künstle et al., 1997), and liver-specific ablation of caspase-8 is protective against anti-CD95-induced liver damage (Kang et al., 2004). Hence, there is no evidence to date that liver cells can undergo RIPK3-dependent necrosis; rather, they seem to be refractory to this type of cell death.
Caspase-8 or cellular FLICE-like inhibitor protein (cFLIP) deficiency leads to embryonic lethality in mice due to defects in endothelial tissues. Caspase-8^−/− and receptor-interacting protein kinase-3 (RIPK3)^−/−, but not cFLIP^−/− and RIPK3^−/−, double-knockout animals develop normally, indicating that caspase-8 antagonizes the lethal effects of RIPK3 during development. Here, we show that the acute deletion of caspase-8 in the gut of adult mice induces enterocyte death, disruption of tissue homeostasis, and inflammation, resulting in sepsis and mortality. Likewise, acute deletion of caspase-8 in a focal region of the skin induces local keratinocyte death, tissue disruption, and inflammation. Strikingly, RIPK3 ablation rescues both phenotypes. However, acute loss of cFLIP in the skin produces a similar phenotype that is not rescued by RIPK3 ablation. TNF neutralization protects from either acute loss of caspase-8 or cFLIP. These results demonstrate that caspase-8-mediated suppression of RIPK3-induced death is required not only during development but also for adult homeostasis. Furthermore, RIPK3-dependent inflammation is dispensable for the skin phenotype.
Cytokines in liver, biliary, and pancreatic disease
2012, Blumgart's Surgery of the Liver, Biliary Tract and Pancreas
Resolution of inflammation-related apoptotic processes by the synthetic tellurium compound, AS101 following liver injury
2009, Journal of Hepatology
Fulminant hepatic failure is a dangerous condition, which occurs when large parts of the liver become damaged beyond repair, and the liver is no longer able to function. This syndrome is induced by inflammatory processes, resulting in acute liver failure. Recently, the organotellurium compound, trichloro(dioxoethylene-O,O^′) tellurate (AS101), has been found by our group to be able to directly inhibit caspases, due to its Te(IV)–thiol chemistry. The aim of this study was to examine the potential of AS101 as an anti-inflammatory and anti-apoptotic compound in vitro and in vivo following liver injury.
Propionibacterium acnes-primed LPS-induced liver injury was performed in Balb/c mice. ALT/AST, cytokines, caspase-1,-3 and-8 activities, and liver histology were assessed.
AS101 inhibited TNFα or anti-FAS-induced apoptotic processes in hepatocytes in vitro. A P. acnes + LPS in vivo liver injury model revealed lower serum ALT and AST and reduced necrosis and apoptosis in AS101-treated mice. IL-18 and IL-1β reduced levels in AS101-treated mice were associated with caspase-1 activity inhibition. Our findings suggest IL-6, IL-17 and pSTAT3 as additional novel players in the pathogenicity of FHF. Inhibition of caspase-3, and-8 activities by AS101 treatment contributed to decreased hepatocyte death, resulting in increased survival.
We suggest that due to its interaction with key-target cysteine residues, AS101 mediates anti-inflammatory and anti-apoptotic effects in this FHF model, which may serve as a potent treatment for mitigation of hepatic damage.

View all citing articles on Scopus

View full text

Research paperICE-protease inhibitors block murine liver injury and apoptosis caused by CD95 or by TNF-α

Abstract

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Cell

Cell

J. Biol. Chem.

Cell

Science

Hepatology

J. Exp. Med.

Transplantation

J. Exp. Med.

Biochem. Pharmacol.

J. Immunol.

Am. J. Pathol.

Research paper
ICE-protease inhibitors block murine liver injury and apoptosis caused by CD95 or by TNF-α