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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.

Author information

1
Department of Gastroenterology, University Hospital Heidelberg, Germany.
2
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
3
Center for Cell Death, Cancer and Inflamation (CCCI), University College London, United Kingdom.
4
Department of Gastroenterology, University Hospital Heidelberg, Germany. Electronic address: tom.ganten@med.uni-heidelberg.de.

Abstract

BACKGROUND AND AIMS:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

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

PMID:
24268735
DOI:
10.1016/j.prp.2013.10.005
[Indexed for MEDLINE]
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