Micro RNA-155 controls Toll-like receptor 3- and hepatitis C virus-induced immune responses in the liver.

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 mi R-155 on poly I: C-activated murine ( C57 BL/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 mi R-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-κ B 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 mi R-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 mi R-155 was elevated in chronically infected patients with HCV, was associated with an IL-28 B SNP (rs12979860) and was inversely correlated with HCV serum load and ISG expression levels. As mi R-155 is a key regulator of anti-inflammatory mechanisms that control innate and adaptive hepatic immune responses during HCV infection, mi R-155 based therapies may represent a novel mechanism to control HCV in the future. [ABSTRACT FROM AUTHOR]