IFN-? Inhibits MiR-122 Transcription through a Stat3-HNF4? Inflammatory Feedback Loop in an IFN-? Resistant HCV Cell Culture System.

ABSTRACT: BACKGROUND:HCV replication in persistently infected cell culture remains resistant to IFN-?/RBV combination treatment, whereas IFN-?1 induces viral clearance. The antiviral mechanisms by which IFN-?1 induces sustained HCV clearance have not been determined. AIM:To investigate the mechanisms by which IFN-? clears HCV replication in an HCV cell culture model. METHODS:IFN-? sensitive (S3-GFP) and resistant (R4-GFP) cells were treated with equivalent concentrations of either IFN-? or IFN-?. The relative antiviral effects of IFN-? and IFN-?1 were compared by measuring the HCV replication, quantification of HCV-GFP expression by flow cytometry, and viral RNA levels by real time RT-PCR. Activation of Jak-Stat signaling, interferon stimulated gene (ISG) expression, and miRNA-122 transcription in S3-GFP and R4-GFP cells were examined. RESULTS:We have shown that IFN-?1 induces HCV clearance in IFN-? resistant and sensitive replicon cell lines in a dose dependent manner through Jak-Stat signaling, and induces STAT 1 and STAT 2 activation, ISRE-luciferase promoter activation and ISG expression. Stat 3 activation is also involved in IFN-?1 induced antiviral activity in HCV cell culture. IFN-?1 induced Stat 3 phosphorylation reduces the expression of hepatocyte nuclear factor 4 alpha (HNF4?) through miR-24 in R4-GFP cells. Reduced expression of HNF4? is associated with decreased expression of miR-122 resulting in an anti-HCV effect. Northern blot analysis confirms that IFN-?1 reduces miR-122 levels in R4-GFP cells. Our results indicate that IFN-?1 activates the Stat 3-HNF4? feedback inflammatory loop to inhibit miR-122 transcription in HCV cell culture. CONCLUSIONS:In addition to the classical Jak-Stat antiviral signaling pathway, IFN-?1 inhibits HCV replication through the suppression of miRNA-122 transcription via an inflammatory Stat 3-HNF4? feedback loop. Inflammatory feedback circuits activated by IFNs during chronic inflammation expose non-responders to the risk of hepatocellular carcinoma.

SUBMITTER: Aboulnasr F 

PROVIDER: S-EPMC4686105 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature