Abstract
Transcription factor MafB regulates differentiation and activity of monocytes/macrophage and is associated with the development of atherosclerosis and cancers. However, the role of MafB in modulation of CD14+ monocytes in chronic viral hepatitis was not fully elucidated. Thus, the aim of current study was to investigate the immunoregulatory function of MafB to type I interferon (IFN) secretion by CD14+ monocytes and its contribution to pathogenesis of chronic hepatitis C virus (HCV) infection. A total of 29 chronic hepatitis C patients and 21 healthy individuals were enrolled. Serum IFN-α1 and IFN-β was measured by ELISA, while MafB mRNA and protein expression were assessed by real-time PCR and Western blot. MafB siRNA or MafB expression plasmid was transfected into purified CD14+ monocytes to suppress or increase MafB expression. The function of MafB siRNA transfected CD14+ monocytes to HCV in cell culture (HCVcc)-infected Huh7.5 cells or CD4+ T cells was also investigated in direct and indirect contact co-culture system. Serum IFN-α1 and IFN-β was robustly reduced in chronic hepatitis C patients. By contrast, MafB was notably elevated in chronic hepatitis C patients and negatively correlated with serum IFN-α1. Overexpression of MafB reduced the IFN-α1 production by CD14+ monocytes from healthy individuals. However, MafB inhibition elevated IFN-α1 secretion by CD14+ monocytes and interferon regulatory factor 3 phosphorylation in chronic hepatitis C. MafB inhibition also promoted CD14+ monocytes-induced viral clearance in HCVcc-infected Huh7.5 cells by up-regulation of IFN-α1 and IFN-β without increasingly destroying hepatocytes, however, did not affect CD14+ monocytes-induced CD4+ T cells differentiation in chronic hepatitis C patients. The current data revealed that overexpression of MafB in chronic hepatitis C patients might suppress type I IFN production by CD14+ monocytes, leading to the viral persistence. MafB might be a potential therapeutic target for treatment of chronic hepatitis C.
Highlights
Hepatitis C virus (HCV) chronically infects approximate 1.8 million persons all over the world, leading to millions of deaths due to the induction of end-stage liver diseases, such as decompensated liver cirrhosis, liver failure, and hepatocellular carcinoma (HCC; Negro, 2014; Lin et al, 2017; Yuan et al, 2017)
A 105 of purified CD14+ monocytes were transfected with control siRNA or MafB siRNA, respectively
Inhibition of MafB in CD14+ monocytes purified from chronic hepatitis C patients induced elevated IFN-α1 secretion, which was accompanied by IRF3 phosphorylation
Summary
Hepatitis C virus (HCV) chronically infects approximate 1.8 million persons all over the world, leading to millions of deaths due to the induction of end-stage liver diseases, such as decompensated liver cirrhosis, liver failure, and hepatocellular carcinoma (HCC; Negro, 2014; Lin et al, 2017; Yuan et al, 2017). We hypothesized that MafB-induced type I IFN reduction in CD14+ monocytes might take part in the formation of viral persistence in patients with chronic hepatitis C. About 0.5 μg of siRNA was transfected into CD14+ monocytes from chronic hepatitis C patients using Lipofectamine 2000 (Invitrogen Thermofisher, Carlsbad, CA, USA) according to the instructions of manufacturer. 105 of CD14+ monocytes were co-cultured with 5 × 105 of HCVcc infected Huh7.5 cells in both direct and indirect contact manners. Cytokine expressions in serum and cultured supernatants were measured using commercial ELISA kits (Beyotime, Wuhan, Hubei Province, China) according to the instructions of manufacturer. Target HCVcc infected Huh7.5 cell death was determined by measuring lactate dehydrogenase (LDH) expression in the cultured supernatants using LDH Cytotoxicity Assay Kit (Beyotime) according to the instructions of manufacturer. All tests were two tails, and p less than 0.05 was considered to indicate significant differences
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