Interferon-Mediated Cytokine Induction Determines Sustained Virus Control in Chronic Hepatitis C Virus Infection.
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and associated complications such as liver cirrhosis and hepatocellular carcinoma. Interferons (IFNs) are crucial for HCV clearance and a sustained virological response (SVR), but a significant proportion of patients do not respond to IFNα. The underlying mechanisms of an insufficient IFN response remain largely unknown. In this study, we found that patients responding to IFNα with viral clearance had significantly higher serum levels of TNF-related apoptosis inducing ligand (TRAIL), compared with patients who failed to control HCV. In addition, upon direct IFNα exposure, peripheral blood mononuclear cells (PBMCs) from patients with SVR upregulated TRAIL, as well as IFN-γ and the chemokines CXCL9 and CXCL10, much more strongly than cells from patients with antiviral treatment failure. As a possible mechanism of the stronger IFNα-induced cytokine response, we identified higher levels of expression and phosphorylation of the transcription factor STAT1 in PBMCs from patients with SVR. Increased TRAIL expression additionally involved the NF-κB and JNK signaling pathways. Thus, SVR in chronic HCV infection is associated with a strong IFNα-induced cytokine response, which might allow for the early prediction of treatment efficacy in HCV infection.
Department of Gastroenterology, Hepatology, and Endocrinology.
Franziska
F
Wandrer
Institute of Transplant Immunology, IFB-Tx.
Christine S
CS
Falk
Department of Gastroenterology, Hepatology, and Endocrinology.
Katharina
K
John
Institute for Cell and Molecular Pathology, Hannover Medical School.
Britta
B
Skawran
Department of Gastroenterology, Hepatology, and Endocrinology.
Michael P
MP
Manns
Interfaculty Institute for Biochemistry, University of Tübingen German Cancer Consortium (DKTK)German Research Cancer Center (DKFZ), Heidelberg, Germany.
Klaus
K
Schulze-Osthoff
Department of Gastroenterology, Hepatology, and Endocrinology.
Heike
H
Bantel
D000328:Adult; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D016174:Hepacivirus / Q000187:drug effects*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D016898:Interferon-alpha / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear; D008099:Liver / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000502:physiology; D017211:Treatment Failure
D016207:Cytokines; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D051550:I-kappa B Kinase; D048670:MAP Kinase Kinase 4
HCV; IFNα; TRAIL; apoptosis; cytokines