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Pathol Res Pract. 2014 Feb;210(2):83-91. doi: 10.1016/j.prp.2013.10.005. Epub 2013 Nov 7.

Hepatocyte expression of TRAIL pathway regulators correlates with histopathological and clinical parameters in chronic HCV infection.

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Department of Gastroenterology, University Hospital Heidelberg, Germany.
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Center for Cell Death, Cancer and Inflamation (CCCI), University College London, United Kingdom.
Department of Gastroenterology, University Hospital Heidelberg, Germany. Electronic address:



Treatment with pegylated interferon-alpha (PEG-IFN) and ribavirin is the backbone of standard therapy of HCV by mechanisms that are not completely understood. Besides a direct antiviral effect, different immunomodulatory and apoptotic effects have been discussed. Tumor necrosis factor-related apoptosis inducing-ligand (TRAIL) is a member of the tumor necrosis factor (TNF) family with immunomodulatory as well as pro- and antiapoptotic effects and is putatively involved in control of HCV infection. Thus, we analyzed the expression of the TRAIL/TRAIL-receptor system, caspase-8 and cFLIP and examined their prognostic and predictive value for HCV infection and antiviral therapy, respectively.


We immunohistochemically analyzed liver biopsies of 116 therapy-naive HCV patients before treatment with PEG-IFNα and ribavirin in comparison to healthy liver tissue. Expression levels of TRAIL, TRAIL-R1 to TRAIL-R4, caspase-8 and cFLIP were correlated with sustained virologic response (SVR), genotype and staging of chronic hepatitis.


Caspase-8, cFLIP, TRAIL-R2 and TRAIL-R4 were strongly upregulated in HCV patients, whereas TRAIL-R3 was downregulated. SVR correlated with high expression of TRAIL and pro-apoptotic TRAIL-R2 on HCV infected hepatocytes.


Our results suggest a pathophysiological role of TRAIL in both, HCV infection and therapy. Further studies need to elaborate possible TRAIL-related targets for clinical applications.


Apoptosis; CMV; Caspase-8; DR; EBV; EVR; Epstein–Barr virus; FADD; FAS-associated via death domain; HCC; Hepatitis C; IFN; NF-κB; PEG-IFN; PLAD; RBV; RVR; SVR; TNF; TNF-related apoptosis inducing ligand; TRAIL; TRAIL-R1; TRAIL-R2; TRAIL-R3; TRAIL-R4; TRAIL-receptor; TRAIL-receptor 1; TRAIL-receptor 2; TRAIL-receptor 3; TRAIL-receptor 4; cEVR; cFLIP; cellular FLICE/caspase-8-inhibitory protein; complete early viral response; cytomegalovirus; death receptor; early virologic response; hepatocellular carcinoma; interferon; mIgG; mouse IgG; nuclear factor kappa B; pEVR; partial early virologic response; pegylated interferon alpha; preligand assembly domain; rapid virologic response; ribavirin; sustained virologic response; tumor necrosis factor

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