Toll Like Receptors in Chronic Viral Hepatitis – Friend and Foe

Broering, Ruth; Lu, Mengji; Schlaak, J.F.

doi:10.5772/25967

Cited by 2 publications

(1 citation statement)

References 122 publications

(115 reference statements)

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“…Infected cells can recognize viral dsRNA through the Toll‐like receptor (TLR) 3, melanoma‐differentiation‐associated gene 5 (MDA5) or the RNA helicase RIG‐I (retinoic acid‐inducible gene‐I) , leading to the activation of transcription factors including nuclear factor‐κB (NF‐κB) and interferon regulatory factor 3 (IRF‐3) . However, HCV has developed evading strategies to subvert this antiviral defence .…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‐155 controls Toll‐like receptor 3‐ and hepatitis C virus‐induced immune responses in the liver

Jiang

Broering

Trippler

et al. 2013

Journal of Viral Hepatitis

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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.

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Section: Introductionmentioning

confidence: 99%

MicroRNA‐155 controls Toll‐like receptor 3‐ and hepatitis C virus‐induced immune responses in the liver

Jiang

Broering

Trippler

et al. 2013

Journal of Viral Hepatitis

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Chemical modifications on siRNAs avoid Toll-like-receptor-mediated activation of the hepatic immune system in vivo and in vitro

Broering

Real

John³

et al. 2013

International Immunology

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Our data indicate that siRNAs activate endosomal Toll-like receptors in different liver-derived cell types to various degrees, in vitro. LNP-formulated siRNA selectively leads to hepatic knock-down of target genes in vivo. Here, off-target immune responses are restricted to non-parenchymal liver cells. However, 2'-O-methyl modifications of siRNA largely avoid immune-stimulatory effects, which is a crucial prerequisite for the development of safe and efficient RNA-interference-based therapeutics.

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Toll Like Receptors in Chronic Viral Hepatitis – Friend and Foe

Cited by 2 publications

References 122 publications

MicroRNA‐155 controls Toll‐like receptor 3‐ and hepatitis C virus‐induced immune responses in the liver

MicroRNA‐155 controls Toll‐like receptor 3‐ and hepatitis C virus‐induced immune responses in the liver

Chemical modifications on siRNAs avoid Toll-like-receptor-mediated activation of the hepatic immune system in vivo and in vitro

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