Transcriptional Dysregulation of Upstream Signaling of IFN Pathway in Chronic HCV Type 4 Induced Liver Fibrosis

• Published in: PloS one 2016-05, Vol.11 (5), p.e0154512-e0154512
• Main Authors: Ibrahim, Marwa K, Salum, Ghada Maher, Bader El Din, Noha G, Dawood, Reham M, Barakat, Ahmed, Khairy, Ahmed, El Awady, Mostafa K
• Format: Article
• Language: English
• Subjects: Adult; Alcohol; Biology and Life Sciences; Biomarkers; Biopsy; Biotechnology; Cellular signal transduction; Consent; Cytokines; Ethics; Experiments; Female; Fibrosis; Gene expression; Genes; Genetic engineering; Genotype & phenotype; Hepacivirus - pathogenicity; Hepatitis; Hepatitis C; Hepatitis C virus; Hepatitis C, Chronic - genetics; Hepatology; Humans; Immunoglobulins; Infections; Inflammation; Interferon; Interferon regulatory factor 7; Leukocytes (mononuclear); Leukocytes, Mononuclear - metabolism; Liver; Liver - metabolism; Liver - virology; Liver Cirrhosis - genetics; Liver diseases; Male; Medicine and health sciences; MyD88 protein; Patients; Peripheral blood mononuclear cells; Polymerase Chain Reaction; Replication; Research and Analysis Methods; Review boards; Ribonucleic acid; Risk factors; RNA; Rodents; Signal Transduction; Signaling; Studies; Substance abuse treatment; TLR7 protein; Toll-like receptors; Transcription (Genetics); Transcription factors; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0154512

IFN orchestrates the expression of various genes to halt hepatitis C virus (HCV) replication with the possibility of either reduced or increased liver fibrosis; due to controlled viral replication or overproduction of inflammatory mediators, repectively. In this study, we examined the transcriptional profiling of type I IFN related genes in HCV-chronically infected patients with varying degrees of liver fibrosis. PCR array was used to examine the expression of 84 type I IFN related genes in peripheral blood mononuclear cells (PBMCs) RNA from 12 treatment-naïve chronic HCV patients (5 F0-F1 and 7 F2-F4) and 5 healthy subjects. We further validated our results by quantitative real time PCR (qRT-PCR) in 103 treatment-naïve chronic HCV patients (43 F0-F1 and 60 F2-F4) and 15 controls. PCR array data revealed dysregulation in TLR7 pathway. The expression of TLR7 was decreased by 4 folds and MyD88 was increased by 3 folds in PBMCs of F2-F4 patients when compared to the healthy volunteers (p = 0.03 and 0.002, respectively). In addition, IRF7 and TLR7 showed dramatic downregulation (6 and 8 folds, respectively) in F2-F4 patients when compared to F0-F1 ones. qRT-PCR confirmed the altered expression patterns of TLR7 and MyD88 in F2-F4 patients when compared to either controls or F0-F1 patients. However, by qRT-PCR, IRF7 and NF-κB1 (TLR7 pathway transcription factors) exhibited similar mRNA abundance among F2-F4 and F0-F1 patients. These results suggest that TLR7 and MyD88 are possible candidates as biomarkers for the progression of HCV-induced liver fibrosis and/ or targets for therapeutic intervention.