title: MicroRNA-155 controls Toll-like receptor 3- and hepatitis C virus-induced immune responses in the liver.
abstract: The hepatitis C virus (HCV) establishes persistent infections despite strong activation of the innate immune system through TLR3 and other sensors. Therefore, we analysed regulatory mechanisms of TLR3-induced immune responses in nonparenchymal liver cells (NPCs). Effects of Interleukin-10 (IL-10), transforming growth factor beta (TGF-β) and immunoregulatory miR-155 on poly I:C-activated murine (C57BL/6) Kupffer cells (KC) and sinusoidal endothelial cells (LSEC) were assessed in vitro. NPCs were assayed for inflammatory and antiviral cytokines and T-cell (Balb/c)-activating factors. Gene expression of miR-155, IL-10, TGF-β and interferon sensitive genes (ISGs) in biopsies of patients with HCV was determined by qrt-PCR. TLR3-induced antiviral activity in murine NPCs was potently suppressed by IL-10 and TGF-β which correlated with decreased TLR3 expression and inhibition of NF-κB and IRF-3 activation. T-cell activation, induced by TLR3-activated NPCs, was also suppressed by IL-10 and TGF-β, which was associated with a down-regulation of CD80 and CD86. Pretreatment with IL-10 or TGF-β suppressed TLR3-induced miR-155 expression, which itself positively regulated poly I:C-mediated immune responses, thus counteracting IL-10 or TGF-β-induced immunosuppression. In addition, hepatic expression of miR-155 was elevated in chronically infected patients with HCV, was associated with an IL-28B SNP (rs12979860) and was inversely correlated with HCV serum load and ISG expression levels. As miR-155 is a key regulator of anti-inflammatory mechanisms that control innate and adaptive hepatic immune responses during HCV infection, miR-155 based therapies may represent a novel mechanism to control HCV in the future.
authors.affiliation: Faculty of Medicine, Department of Gastroenterology and Hepatology, University Duisburg-Essen, Essen, Germany; Faculty of Medicine, Institute of Virology, University Duisburg-Essen, Essen, Germany; Department of Infectious Disease, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: M
authors.initials: M
authors.lastname: Jiang
authors.forename: R
authors.initials: R
authors.lastname: Broering
authors.forename: M
authors.initials: M
authors.lastname: Trippler
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.forename: E
authors.initials: E
authors.lastname: Zhang
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: G
authors.initials: G
authors.lastname: Gerken
authors.forename: M
authors.initials: M
authors.lastname: Lu
authors.forename: J F
authors.initials: JF
authors.lastname: Schlaak
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000276:immunology; D020869:Gene Expression Profiling; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D007728:Kupffer Cells / Q000276:immunology; D008099:Liver / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000276:immunology*
chemical_list: C524942:MIRN155 microRNA, human; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; C495344:TLR3 protein, human; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3
keywords: Kupffer cells; hepatitis C virus; interleukin-10; liver sinusoidal endothelial cells; miR-155; transforming growth factor beta