Abstract
Objective: The present study aims to identify the differently expressed microRNA (miRNA) molecules and target genes of miRNA in the immune tolerance (IT) and immune activation (IA) stages of chronic hepatitis B (CHB). Methods: miRNA expression profiles of peripheral blood mononuclear cells (PBMCs) at the IT and IA stages of CHB were screened using miRNA microarrays and authenticated using a quantitative real-time polymerase chain reaction (RT-PCR). Gene ontology (GO) and the Kyoto encyclopedia of genes and genomes (KEGG) were used to analyze the significant functions and pathways of possible target genes of miRNAs. Assays of the gain and loss of function of the miRNAs were performed to verify the target genes in THP-1 cell lines. The luciferase reporter test was used on 293T cells as direct targets. Results: Significantly upregulated miR-548 and miR-4804 were observed in the miRNA microarrays and confirmed by RT-PCR in PBMCs at the IT and IA stages of CHB. GO and KEGG analysis revealed that MiR-548 and miR-4804 could be involved in numerous signaling pathways and protein binding activity. IFNγR1 was predicted as a target gene and validated as the direct gene of MiR-548. Significant negative correlation was found between the miR-548ah and mRNA levels of IFN-γR1 in CHB patients. Conclusions: The abnormal expression profiles of miRNA in PBMCs could be closely associated with immune activation of chronic HBV infection. miR-548, by targeting IFN-γR1, may represent a mechanism that can facilitate viral pathogenesis and help determine new therapeutic molecular targets.
Highlights
The Hepatitis B virus (HBV) infection remains a serious public health problem worldwide despite the wide use of the HBV vaccine
Compared with the normal controls, 2 significantly upregulated and 18 significantly downregulated miRNA molecules were identified in peripheral blood mononuclear cells (PBMCs) during the immune tolerance (IT) phase of chronic hepatitis B (CHB); 33 significantly upregulated and 19 significantly downregulated miRNA molecules were identified in PBMCs during the immune activation (IA) phase of CHB
Some studies have reported that the interaction between certain miRNAs and HBV has an important function in the pathogenesis of chronic HBV infection [18,19]
Summary
The Hepatitis B virus (HBV) infection remains a serious public health problem worldwide despite the wide use of the HBV vaccine. The host immune response, especially the virus-specific T cell response, plays an important role in the viral clearance and pathogenesis of liver diseases [2,3]. Patients suffering from chronic hepatitis B (CHB) have weak and limited T cell responses, whereas those with acute hepatitis have vigorous and polyclonal T cell responses, which can help them completely clear the virus [4]. The lack of virus-specific T cell response in the former case might be attributed to various factors, such as T cell deletion, anergy, exhaustion, ignorance, and T cell dysfunction [5], but the exact mechanism is not yet clear. Impairment of functions of dendritic cells, natural killer cells, and natural killer T cells occur during chronic HBV infection [6,7]
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