Involvement of TRAIL and its receptors in viral hepatitis

Mundt, Bettina; Kühnel, Florian; Zender, Lars; Paul, Yasmin; Tillmann, Hans L.; Trautwein, Christian; Manns, Michael P.; Kubicka, Stefan

doi:10.1096/fj.02-0537fje

Cited by 133 publications

(114 citation statements)

References 42 publications

(60 reference statements)

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“…To determine whether innate immune cells were required for tumour clearance, mice bearing subcutaneous hepatocarcinomas harbouring the conditional p53 shRNA were treated with gadolinium chloride (a macrophage toxin) 19,20 or neutralizing antibodies to suppress neutrophil or natural killer cell function 20,21 , and monitored for tumour regression following Dox treatment. All three treatments significantly delayed tumour regression following p53 reactivation (Fig.…”

mentioning

confidence: 99%

Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas

Xue

Zender

Miething

et al. 2007

Nature

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Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence 1,2 . Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies 3 . To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma 4,5 . We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth.p53 mutations are common in human liver cancer 6 , which is typically highly aggressive and resistant to non-surgical therapies. To determine the requirement for p53 loss in the maintenance of such carcinomas, we used reversible RNAi 7 to control p53 in a chimaeric liver cancer mouse model (Fig. 1a) 4,5 . Purified embryonic liver progenitor cells (hepatoblasts) were transduced with retroviruses expressing oncogenic ras (HrasV12), the tetracycline transactivator protein tTA ('tet-off') and a tet-responsive p53 miR30 design short hairpin RNA (shRNA; Supplementary Fig. 1a) 7,8 , and seeded into the livers of athymic nude mice following intrasplenic injection 4,5 . To facilitate in vivo imaging, the oncogenic ras retrovirus co-expressed green fluorescent protein (GFP) and, in some experiments, hepatoblasts were also co-transduced with a luciferase reporter.p53 expression was efficiently suppressed in the absence of doxycycline (Dox) and rapidly restored following Dox addition ( Supplementary Fig. 1b, c). On transplantation into the livers of recipient mice, hepatoblast populations co-expressing Ras and the conditional p53 shRNA rapidly produced invasive hepatocarcinomas in the absence of Dox (Fig. 1b), whereas cells expressing each vector alone did not (data not shown). These tumours were GFP-positive and, if expressing luciferase, could be visualized externally by bioluminescence imaging (Fig. 1b).

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mentioning

confidence: 99%

Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas

Xue

Zender

Miething

et al. 2007

Nature

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2,187

1,885

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“…Adenovirus preparation and viral plaquing were performed as described (5,6). AdFasL was administered via tail vein in a dose of 6.25 ϫ 10 7 pfu͞g of body weight.…”

Section: Adenovirus Preparation and In Vivo Infection Experimentsmentioning

confidence: 99%

“…Mice injected with agonistic Fas (CD95) antibody rapidly develop ALF and die within hours (3). In animal models of acute viral hepatitis, apoptosis of hepatocytes is mediated by death receptors such as Fas (CD95), tumor necrosis factor (TNF)␣, and TNFrelated apoptosis-inducing ligand (4)(5)(6), and several studies in humans showed that apoptosis of hepatocytes in Wilson's disease, toxic liver damage, and viral hepatitis is triggered through death receptors (7,8). Consequently an attractive strategy to treat patients with ALF would be to inhibit death receptor-mediated apoptosis to maintain liver function and save the organ.…”

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confidence: 99%

Caspase 8 small interfering RNA prevents acute liver failure in mice

Zender

Hütker²,

Liedtke³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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A major concern in therapy of acute liver failure is protection of hepatocytes to prevent apoptosis and maintain liver function. Small interfering RNA (siRNA) is a powerful tool to silence gene expression in mammalian cells. To evaluate the therapeutic efficacy of siRNA in vivo we used different mouse models of acute liver failure. We directed 21-nt siRNAs against caspase 8, which is a key enzyme in death receptor-mediated apoptosis. Systemic application of caspase 8 siRNA results in inhibition of caspase 8 gene expression in the liver, thereby preventing Fas (CD95)-mediated apoptosis. Protection of hepatocytes by caspase 8 siRNA significantly attenuated acute liver damage induced by agonistic Fas (CD95) antibody (Jo2) or by adenovirus expressing Fas ligand (AdFasL). However, in a clinical situation the siRNAs most likely would be applied after the onset of acute liver failure. Therefore we injected caspase 8 siRNA at a time point during AdFasL-and adenovirus wild type (Adwt)-mediated liver failure with already elevated liver transaminases. Improvement of survival due to RNA interference was significant even when caspase 8 siRNA was applied during ongoing acute liver failure. In addition, it is of particular interest that caspase 8 siRNA treatment was successful not only in acute liver failure mediated by specific Fas agonistic agents (Jo2 and AdFasL) but also in acute liver failure mediated by Adwt, which is an animal model reflecting multiple molecular mechanisms involved in human acute viral hepatitis. Consequently, our data raise hope for future successful application of siRNA in patients with acute liver failure.

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“…46 In hepatocytes, TRAIL-mediated apoptosis in vivo has been shown to depend on triggering through viral infection. 47 Thus, endogenous overexpression of TRAIL seems to enable the organism to selectively eliminate virally infected hepatocytes. TRAIL and its receptors in mouse hepatitis models display up-regulation in adenovirus infection, and liver cells have been demonstrated to be sensitized toward TRAIL-induced cytotoxicity by HBV replication in vitro.…”

Section: Function Of Trail and Its Receptors In Liver Diseasementioning

confidence: 99%

“…In patients with chronic hepatitis B, HBV infection may increase serum TRAIL, 48 and HBV-infected hepatocytes can be killed by up-regulated TRAIL. 47 Recently, Higuchi et al [49][50][51] reported that bile acids up-regulate TRAIL-R2 expression, and Zheng et al 52 demonstrated the essential contribution of TRAIL in concanavalin A-induced and Listeria-induced liver injury, indicating that TRAIL is also an important mediator of apoptosis in nonviral liver disease. Surprisingly, Mundt et al 53 recently reported that TRAIL expression in virally infected livers of mice not only induced apoptosis of infected hepatocytes but also led to steatosis, a characteristic feature of liver diseases such as chronic hepatitis C, alcoholic liver disease, and nonalcoholic steatohepatitis.…”

Section: Function Of Trail and Its Receptors In Liver Diseasementioning

confidence: 99%

On the TRAIL to therapeutic intervention in liver disease

2007

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Hepatocellular carcinoma (HCC) ranks among the 10 most common cancers worldwide. The fact that HCC is resistant to conventional chemotherapy and is rarely amenable to radiotherapy leaves this disease with no effective therapeutic options and a very poor prognosis. Therefore, the development of more effective therapeutic tools and strategies is much needed. HCCs are phenotypically and genetically heterogeneous tumors that commonly emerge on a background of chronic liver diseases, most of which culminate in cirrhosis, such as alcoholic cirrhosis and chronic hepatitis B and C infections. This review outlines recent findings on the progression of liver disease, including our knowledge of the role of apoptotic processes, with an emphasis on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The proapoptotic and antiapoptotic properties of TRAIL, its involvement in liver injury, and its potential as a therapeutic agent in fibrosis and HCC are discussed. Several contradictory and confusing data have not yet been resolved or placed into perspective, such as the influence of factors that determine the TRAIL sensitivity of target cells, including the tumor microenvironment or cirrhotic tissue. Therefore, we assess these data from the perspectives of gastroenterologists (P.S. and M.W.B.) and a molecular oncologist (I.H.) with research interests in liver injury, apoptosis, and experimental therapeutics. (HEPATOLOGY

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Involvement of TRAIL and its receptors in viral hepatitis

Cited by 133 publications

References 42 publications

Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas

Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas

Caspase 8 small interfering RNA prevents acute liver failure in mice

On the TRAIL to therapeutic intervention in liver disease

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