Micro RNA ‐155 controls T oll‐like receptor 3‐ and hepatitis C virus‐induced immune responses in the liver

Summary The hepatitis C virus ( HCV ) establishes persistent infections despite strong activation of the innate immune system through TLR 3 and other sensors. Therefore, we analysed regulatory mechanisms of TLR 3‐induced immune responses in nonparenchymal liver cells ( NPC s). Effects of Interleukin‐10 ( IL ‐10), transforming growth factor beta ( TGF ‐β) and immunoregulatory mi R ‐155 on poly I : C ‐activated murine ( C 57 BL /6) K upffer cells ( KC ) and sinusoidal endothelial cells ( LSEC ) were assessed in vitro . NPC s were assayed for inflammatory and antiviral cytokines and T ‐cell ( B alb/c)‐activating factors. Gene expression of mi R ‐155, IL ‐10, TGF ‐β and interferon sensitive genes ( ISG s) in biopsies of patients with HCV was determined by qrt‐ PCR . TLR 3‐induced antiviral activity in murine NPC s was potently suppressed by IL ‐10 and TGF ‐β which correlated with decreased TLR 3 expression and inhibition of NF ‐κ B and IRF ‐3 activation. T‐cell activation, induced by TLR 3‐activated NPC s, was also suppressed by IL ‐10 and TGF ‐β, which was associated with a down‐regulation of CD 80 and CD 86. Pretreatment with IL ‐10 or TGF ‐β suppressed TLR 3‐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.