Critical roles of TRAIL in hepatic cell death and hepatic inflammation

Zheng, Shijun; Wang, Pu; Tsabary, Galit; Chen, Youhai H.

doi:10.1172/jci19255

Cited by 110 publications

(125 citation statements)

References 28 publications

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“…49 This is in accordance with experimental models of hepatitis, in which hepatic cell death was strongly reduced in TRAILdeficient mice or mice treated with a blocking TRAIL receptor. 50 Thus, it seems that the ability of TRAIL to induce apoptosis in hepatocytes might strongly depend on the inflammatory context. This view is supported by the recent observation that TRAIL is highly synergistic with CD95L in the induction of hepatocyte apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…PHHs were isolated from healthy liver as described 27 and provided by Cytonet (Hannover, Germany). For the culture of isolated hepatocytes and liver tissue, we used modified Eagle's medium (Biochrom, Berlin, Germany) supplemented with 1% human serum, 0.4 IE/mL insulin, 20 mM HEPES [4- 50 mg/L ascorbic acid, 50 g/mL gentamycin, and 8 g/mL dexamethasone. Isolated hepatocytes were maintained in medium for 16 hours at 37°C in 5% CO 2 prior to incubation with the apoptotic stimuli, whereas incubation of liver tissue was performed immediately.…”

Section: Methodsmentioning

confidence: 99%

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Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver

Fischer²,

et al. 2007

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in tumor cells but not in most normal cells and has therefore been proposed as a promising antitumor agent. Recent experiments suggested that isolated primary human hepatocytes but not monkey liver cells are susceptible to certain TRAIL agonists, raising concerns about the use of TRAIL in cancer treatment. Whether TRAIL indeed exerts hepatotoxicity in vivo and how this is influenced by chemotherapeutic drugs or liver disease are completely unknown. Employing different forms of recombinant TRAIL, we found that the cytokine can induce proapoptotic caspase activity in isolated human hepatocytes. However in marked contrast, these different TRAIL preparations induced little or no cytotoxicity when incubated with tissue explants of fresh healthy liver, an experimental model that may more faithfully mimic the in vivo situation. In healthy liver, TRAIL induced apoptosis only when combined with histone deacetylase inhibitors. Strikingly, however, TRAIL alone triggered massive apoptosis accompanied by caspase activation in tissue explants from patients with liver steatosis or hepatitis C viral infection. This enhanced sensitivity of diseased liver was associated with an increased expression of TRAIL receptors and up-regulation of proapoptotic Bcl-2 proteins. Conclusion: These results suggest that clinical trials should be performed with great caution when TRAIL is combined with chemotherapy or administered to patients with inflammatory liver diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver

Fischer²,

et al. 2007

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“…2 TRAIL has also a crucial role in Con A-induced hepatitis. 3 TRAIL activates apoptosis by binding to death receptors DR4 (TRAIL-R1) and DR5 (TRAIL-R2) 4 in humans and only to mDR5 (mTRAIL-R2/mKILLER) in mice. 5 Besides apoptosis induction, TRAIL induces necrosis in Jurkat cells 6 or in murine prostate adenocarcinoma TRAMP-C2 cells.…”

Section: Tumor Necrosis Factor (Tnf)-related Apoptosis Inducing Liganmentioning

confidence: 99%

TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation

et al. 2012

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Although TRAIL (tumor necrosis factor (TNF)-related apoptosis inducing ligand) is a well-known apoptosis inducer, we have previously demonstrated that acidic extracellular pH (pHe) switches TRAIL-induced apoptosis to regulated necrosis (or necroptosis) in human HT29 colon and HepG2 liver cancer cells. Here, we investigated the role of RIPK1 (receptor interacting protein kinase 1), RIPK3 and PARP-1 (poly (ADP-ribose) polymerase-1) in TRAIL-induced necroptosis in vitro and in concanavalin A (Con A)-induced murine hepatitis. Pretreatment of HT29 or HepG2 with pharmacological inhibitors of RIPK1 or PARP-1 (Nec-1 or PJ-34, respectively), or transient transfection with siRNAs against RIPK1 or RIPK3, inhibited both TRAILinduced necroptosis and PARP-1-dependent intracellular ATP depletion demonstrating that RIPK1 and RIPK3 were involved upstream of PARP-1 activation and ATP depletion. In the mouse model of Con A-induced hepatitis, where death of mouse hepatocytes is dependent on TRAIL and NKT (Natural Killer T) cells, PARP-1 activity was positively correlated with liver injury and hepatitis was prevented both by Nec-1 or PJ-34. These data provide new insights into TRAIL-induced necroptosis with PARP-1 being active effector downstream of RIPK1/RIPK3 initiators and suggest that pharmacological inhibitors of RIPKs and PARP-1 could be new treatment options for immune-mediated hepatitis.

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“…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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Critical roles of TRAIL in hepatic cell death and hepatic inflammation

Cited by 110 publications

References 28 publications

Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver

Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver

TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation

On the TRAIL to therapeutic intervention in liver disease

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