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TLR3-dependent immunological properties of liver cells are controlled by anti-inflammatory cytokines through modulation of miR-155 expression
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Speaker:
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Ruth Bröring
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Author:
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M. Jiang1, M. Trippler1, R. Broering1*, J. Wu1, E. Zhang2, X. Zhang2, G. Gerken1, M. Lu2, J.F. Schlaak1
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Affiliation:
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1Department of Gastroenterology and Hepatology, University Hospital of Essen, 2Institute of Virology, University Hospital of Essen, Essen, Germany. *ruth.broering@uni-due.de
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Background and aims: The hepatitis C virus (HCV) can establish a persistent infection despite a strong activation of the innate immune system through TLR3 and other sensors, the so-called “IFN-paradox”. We analyzed regulatory mechanisms of TLR3-mediated immune responses in human liver and in murine non-parenchymal liver cells (NPC).
Methods: Hepatic expression of Interleukin 10 (IL-10) and transforming growth factor beta (TGF-β) in biopsies of HCV patients was determined by qrt-PCR and correlated to viral and host parameters. The effect of IL-10, TGF-β and miR-155 on poly I:C-activated murine Kupffer cells (KC) was assessed in vitro. NPC were assayed for inflammatory and antiviral cytokines as well as T cell-activating factors.
Results: Elevated expression of TGF-β was linked to HCV genotype 1, while hepatic IL-10 expression correlated with HCV titers. TLR3-induced antiviral activity of NPC in a murine HCV-replicon system was potently suppressed by IL-10 or TGF-β. This correlated with decreased TLR3 expression and inhibition of NF-κB and IRF-3 activation in NPC. T cell activation, induced by TLR3-activated NPC, was suppressed by IL-10 and TGF-β which was associated with a down-regulation of CD80 and CD86. In primary KC, miR-155 could be up-regulated by poly I:C. Inhibition of NF-κB by Bay11-7082 impaired TLR3-induced miR-155 expression. The expression levels of miR-155, TNF-α, IL-6 and IFI-T1 were elevated after miR-155 mimic treatment compared with controls. Pretreatment with IL-10 or TGF-β potently suppressed TLR3-induced miR-155 expression. The immunosuppressive effects of IL-10 and TGF-β in NPCs could be completely abrogated by treatment with miR-155 mimics.
Conclusions: Our data suggest that TLR3-induced innate and adaptive immune responses in the liver are controlled by anti-inflammatory cytokines which in turn is mediated largely through miR-155. This is of relevance for the regulation of local immune responses and may at least partly explain the “IFN-paradox” in the pathogenesis of HCV infection, in particular.
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