Fas-mediated apoptosis in mouse hepatocytes involves the processing and activation of caspases

Jones, Richard A.; Johnson, Victoria L.; Buck, Neil; Dobrota, Miloslav; Hinton, Richard H.; Chow, Sek C.; Kass, George E.N.

doi:10.1002/hep.510270624

Cited by 87 publications

(60 citation statements)

References 70 publications

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“…Pre-treatment of hepatocytes with broad spectrum caspase inhibitor, z-VAD-FMK and more specific inhibition of caspase-3 (Ac-DEVD-CHO or z-DEVD-FMK), caspase-8 (z-IETD-FMK) and caspase-9 (z-LEHD-FMK) has provided evidence in the same way as had been reported in previously studied cell types and cell lines (Cain et al 1996;Jones et al 1998;Blom et al 1999;Woo et al 1999;Albright et al 2003). Similarly, we show in the present study that staurosporine-induced apoptosis can be blocked by treatment with caspase inhibitors.…”

Section: Discussionsupporting

confidence: 72%

Apoptosis and Its Suppression in Hepatocytes Culture

Mukwena

Al‐Rubeai

2004

Cytotechnology

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In order to achieve the goal of developing extracorporeal liver support devices, it is necessary to optimise bioprocess environment such that viability and function are maximised. Optimising culture medium composition and controlling the constitution of the cellular microenvironment within the bioreactor have for many years been considered vital to achieving these aims. Coupled to this is the need to understand apoptosis, the prime suspect in the demise of animal cultures, including those of hepatocytes. Results presented here show that absent nutrients including glucose and amino acids play a substantial part in the induction of apoptosis. The use of chemical apoptosis inhibitors was utilised to investigate key components of hepatic apoptosis where caspases, predominantly caspase 8, were implicated in staurosporine (STS)-induced HepZ apoptosis. Caspase 9 and 3 activation although recorded was of less significance. Interestingly, these results were not consistent with those of mitochondrial membrane depolarisation where inhibition of caspase activation appeared to drive depolarisation. Inhibition of mitochondrial permeability transition and use of anti-oxidants was unsuccessful in reducing apoptosis, caspase activation and mitochondrial membrane depolarisation. In further studies, the anti-apoptotic gene bcl-2 was over-expressed in HepZ, resulting in a cell line that was more robust and resistant to death induced by glucose and cystine deprivation and treatment with STS. Bcl-2 did not however show significant cytoprotectivity where apoptosis was stimulated by deprivation of glutamine and serum. Overall, results indicated that although apoptosis can be curbed by use of chemical inhibitors and genetic manipulation, their success is dependent on apoptotic stimuli.

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Section: Discussionsupporting

confidence: 72%

Apoptosis and Its Suppression in Hepatocytes Culture

Mukwena

Al‐Rubeai

2004

Cytotechnology

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“…The major organ affected is the liver and the massive hepatocyte apoptosis is responsible for the animal death [11]. Furthermore, isolated hepatocytes are susceptible to anti-Fas antibody induced apoptosis in vitro, demonstrating the direct cytotoxic effects of Fas activation in this type of cells [12]. caspases-3/7 activities are detected in liver cells of mice injected with anti-Fas antibodies as well as in hepatocytes incubated with anti-Fas in vitro [12].…”

Section: The Role Of Bid In Fas-mediated Hepatocyte Apoptosismentioning

confidence: 99%

“…Furthermore, isolated hepatocytes are susceptible to anti-Fas antibody induced apoptosis in vitro, demonstrating the direct cytotoxic effects of Fas activation in this type of cells [12]. caspases-3/7 activities are detected in liver cells of mice injected with anti-Fas antibodies as well as in hepatocytes incubated with anti-Fas in vitro [12]. Furthermore, hepatocytes transgenically over-expressing Bcl-2 are resistant to anti-Fas antibody-induced injury in vivo [13].…”

Section: The Role Of Bid In Fas-mediated Hepatocyte Apoptosismentioning

confidence: 99%

Signal transduction mediated by Bid, a pro-death Bcl-2 family proteins, connects the death receptor and mitochondria apoptosis pathways

2000

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“…FADD in turn activates upstream caspase-8, and the effector caspases involved in apoptosis, caspase-9 and -3. [32][33][34][35] Therefore, this model is more suitable for investigating the action of crmA in the activated lymphocyte-induced hepatocyte apoptosis in hepatitis.…”

Section: Discussionmentioning

confidence: 99%

CrmA gene expression protects mice against concanavalin-A-induced hepatitis by inhibiting IL-18 secretion and hepatocyte apoptosis

et al. 2003

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Activated cytotoxic T-cell-mediated hepatocyte apoptosis via Fas/Fas-ligand and perforin/granzyme pathways are believed to involve the model of concanavalin A (ConA)-induced hepatitis. The purpose of the present study is to investigate whether the cytokine response modifier A (crmA) gene effectively inhibits the hepatocyte apoptosis of ConAinduced hepatitis. We examined survival rates, liver pathology, immune histological changes, and cytokine profiles from mice receiving the recombinant adenovirus vectors containing cre and/or crmA genes, transferred to the liver 3 days before ConA injection, and a crmA gene nonexpression control group. Injection of ConA into mice rapidly led to massive hepatocyte apoptosis, and infiltration of leukocytes, especially CD11b + inflammatory cells. In contrast, liver damage was dramatically reduced in the mice that expressed the crmA gene. However, infiltration by CD4 + cells was not affected. The survival of the mice increased significantly to 100% in the treated group versus the control group. Furthermore, we demonstrated that interleukin (IL)-18 plays an important role in ConA-induced hepatitis, and that crmA expression significantly inhibited IL-18 secretion. Our results showed that the crmA gene effectively inhibits apoptosis induced by ConA hepatitis. This indicates a potential therapeutic usage of crmA for protection from cellular damage due to hepatitis.

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Fas-mediated apoptosis in mouse hepatocytes involves the processing and activation of caspases

Cited by 87 publications

References 70 publications

Apoptosis and Its Suppression in Hepatocytes Culture

Apoptosis and Its Suppression in Hepatocytes Culture

Signal transduction mediated by Bid, a pro-death Bcl-2 family proteins, connects the death receptor and mitochondria apoptosis pathways

CrmA gene expression protects mice against concanavalin-A-induced hepatitis by inhibiting IL-18 secretion and hepatocyte apoptosis

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