title: Role of A20 in interferon-α-mediated functional restoration of myeloid dendritic cells in patients with chronic hepatitis C.
abstract: Hepatitis C virus (HCV) infection is a global health problem characterized by a high rate of chronic infection, which may in part be due to a defect in myeloid dendritic cells (mDCs). This defect appears to be remedied by treatment with interferon-α (IFN-α) -based antiviral therapies; however, the molecular mechanisms underlying mDC dysfunction in HCV infection and restoration by IFN-α treatment are unclear. The ubiquitin-editing protein A20 plays a crucial role in controlling the maturation, cytokine production and immunostimulatory function of mDCs. We propose that the expression of A20 correlates with the function of mDCs during HCV infection and IFN-α therapy. In this study, we observed that A20 expression in mDCs isolated from chronically HCV-infected subjects was significantly higher than healthy subjects or subjects achieving sustained virological responses (SVR) following antiviral treatment. Notably, A20 expression in mDCs from HCV patients during IFN-α treatment was significantly lower than for untreated patients, SVR patients, or healthy subjects. Besides, A20 expression in mDCs stimulated by polyI:C differed between HCV patients and healthy subjects, and this difference could be abrogated by the treatment with IFN-α in vitro. Additionally, A20 expression by polyI:C-activated mDCs, with or without IFN-α treatment, negatively correlated with the expression of HLA-DR, CD86 and CCR7, and the secretion of interleukin-12 (IL-12), but positively associated with the production of IL-10. Importantly, silencing A20 expression using small interfering RNAs increased the production of IL-12 in mDCs of chronically HCV-infected individuals. These findings suggest that A20 plays a crucial role in negative regulation of innate immune responses during chronic viral infection.
authors: Department of Infectious Diseases, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
authors: Li
authors: L
authors: Ma
authors: Yun
authors: Y
authors: Zhou
authors: Ying
authors: Y
authors: Zhang
authors: Yuan
authors: Y
authors: Li
authors: Yonghong
authors: Y
authors: Guo
authors: Yu
authors: Y
authors: He
authors: Jiuping
authors: J
authors: Wang
authors: Jianqi
authors: J
authors: Lian
authors: Chunqiu
authors: C
authors: Hao
authors: Jonathan P
authors: JP
authors: Moorman
authors: Zhi Q
authors: ZQ
authors: Yao
authors: Yongxing
authors: Y
authors: Zhou
authors: Zhansheng
authors: Z
authors: Jia
mesh_terms: D000293:Adolescent; D000328:Adult; D051940:B7-2 Antigen / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D019562:Viral Load; D055815:Young Adult
chemical_list: D051940:B7-2 Antigen; D004268:DNA-Binding Proteins; D006684:HLA-DR Antigens; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D054400:Receptors, CCR7; D016753:Interleukin-10; D018664:Interleukin-12; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
keywords: A20; chronic infection; hepatitis C virus; interferon-α; myeloid dendritic cells