title: Hepatocyte expression of TRAIL pathway regulators correlates with histopathological and clinical parameters in chronic HCV infection.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Gastroenterology, University Hospital Heidelberg, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Brost
authors.affiliation: Department of Gastroenterology, University Hospital Heidelberg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Zimmermann
authors.affiliation: Department of Gastroenterology, University Hospital Heidelberg, Germany.
authors.forename: Ronald
authors.initials: R
authors.lastname: Koschny
authors.affiliation: Department of Gastroenterology, University Hospital Heidelberg, Germany.
authors.forename: Jaromir
authors.initials: J
authors.lastname: Sykora
authors.affiliation: Department of Gastroenterology, University Hospital Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Center for Cell Death, Cancer and Inflamation (CCCI), University College London, United Kingdom.
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
authors.affiliation: Department of Gastroenterology, University Hospital Heidelberg, Germany. Electronic address: tom.ganten@med.uni-heidelberg.de.
authors.forename: Tom M
authors.initials: TM
authors.lastname: Ganten
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D017209:Apoptosis; D053181:Caspase 8 / Q000378:metabolism*; D004359:Drug Therapy, Combination; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D053319:Tumor Necrosis Factor Decoy Receptors / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D058851:GPI-Linked Proteins; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C108661:TNFRSF10C protein, human; C451501:TNFRSF10D protein, human; C505653:TNFSF10 protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D011092:Polyethylene Glycols; D012254:Ribavirin; D053181:Caspase 8; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a
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