title: HCV-induced miR146a controls SOCS1/STAT3 and cytokine expression in monocytes to promote regulatory T-cell development.
abstract: Host innate and adaptive immune responses must be tightly regulated by an intricate balance between positive and negative signals to ensure their appropriate onset and termination while fighting pathogens and avoiding autoimmunity; persistent pathogens may usurp these regulatory machineries to dampen host immune responses for their persistence in vivo. Here, we demonstrate that miR146a is up-regulated in monocytes from hepatitis C virus (HCV)-infected individuals compared to control subjects. Interestingly, miR146a expression in monocytes without HCV infection increased, whereas its level in monocytes with HCV infection decreased, following Toll-like receptor (TLR) stimulation. This miR146a induction by HCV infection and differential response to TLR stimulation were recapitulated in vitro in monocytes co-cultured with hepatocytes with or without HCV infection. Importantly, inhibition of miR146a in monocytes from HCV-infected patients led to a decrease in IL-23, IL-10 and TGF-β expressions through the induction of suppressor of cytokine signalling 1 (SOCS1) and the inhibition of signal transducer and activator transcription 3 (STAT3), and this subsequently resulted in a decrease in regulatory T cells (Tregs) accumulated during HCV infection. These results suggest that miR146a may regulate SOCS1/STAT3 and cytokine signalling in monocytes, directing T-cell differentiation and balancing immune clearance and immune injury during chronic viral infection.
authors.affiliation: Center for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Ren
authors.affiliation: Center for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.|Department of Hepatology, Guangzhou Number 8 People's Hospital, Guangzhou, China.
authors.forename: R S
authors.initials: RS
authors.lastname: Ying
authors.affiliation: Center for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.|International Center for Diagnosis and Treatment of Liver Diseases, 302 Hospital, Beijing, China.
authors.forename: Y Q
authors.initials: YQ
authors.lastname: Cheng
authors.affiliation: Center for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Center for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors.forename: M
authors.initials: M
authors.lastname: El Gazzar
authors.affiliation: Center for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors.forename: G Y
authors.initials: GY
authors.lastname: Li
authors.affiliation: Center for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Ning
authors.affiliation: Center for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.|Hepatitis (HCV/HIV) Program, James H. Quillen VA Medical Center, Johnson City, TN, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Moorman
authors.affiliation: Center for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA. Yao@etsu.edu.|Hepatitis (HCV/HIV) Program, James H. Quillen VA Medical Center, Johnson City, TN, USA. Yao@etsu.edu.
authors.forename: Z Q
authors.initials: ZQ
authors.lastname: Yao
mesh_terms: D016207:Cytokines / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007108:Immune Tolerance; D035683:MicroRNAs / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000096:biosynthesis*; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000096:biosynthesis*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D016207:Cytokines; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; C108944:SOCS1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein
keywords: SOCS1; STAT3; hepatitis C virus; miR146a; monocytes; regulatory T cells