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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

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IFN-λ Inhibits MiR-122 Transcription through a Stat3-HNF4α Inflammatory Feedback Loop in an IFN-α Resistant HCV Cell Culture System.

Aboulnasr Fatma F Hazari Sidhartha S Nayak Satyam S Chandra Partha K PK Panigrahi Rajesh R Ferraris Pauline P Chava Srinivas S Kurt Ramazan R Song Kyongsub K Dash Asha A Balart Luis A LA Garry Robert F RF Wu Tong T Dash Srikanta S

PloS one 20151211 12

<h4>Background</h4>HCV replication in persistently infected cell culture remains resistant to IFN-α/RBV combination treatment, whereas IFN-λ1 induces viral clearance. The antiviral mechanisms by which IFN-λ1 induces sustained HCV clearance have not been determined.<h4>Aim</h4>To investigate the mechanisms by which IFN-λ clears HCV replication in an HCV cell culture model.<h4>Methods</h4>IFN-α sensitive (S3-GFP) and resistant (R4-GFP) cells were treated with equivalent concentrations of either IF ...[more]

PMID: 26657215

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Project description:Hepatitis C virus (HCV) infection compromises the natural defense mechanisms of the liver leading to a progressive end stage disease such as cirrhosis and hepatocellular carcinoma (HCC). The hepatic stress response generated due to viral replication in the endoplasmic reticulum (ER) undergoes a stepwise transition from adaptive to pro-survival signaling to improve host cell survival and liver disease progression. The minute details of hepatic pro-survival unfolded protein response (UPR) signaling that contribute to HCC development in cirrhosis are unknown. This study shows that the UPR sensor, the protein kinase RNA-like ER kinase (PERK), mediates the pro-survival signaling through nuclear factor erythroid 2-related factor 2 (NRF2)-mediated signal transducer and activator of transcription 3 (STAT3) activation in a persistent HCV infection model of Huh-7.5 liver cells. The NRF2-mediated STAT3 activation in persistently infected HCV cell culture model resulted in the decreased expression of hepatocyte nuclear factor 4 alpha (HNF4A), a major liver-specific transcription factor. The stress-induced inhibition of HNF4A expression resulted in a significant reduction of liver-specific microRNA-122 (miR-122) transcription. It was found that the reversal of hepatic adaptive pro-survival signaling and restoration of miR-122 level was more efficient by interferon (IFN)-based antiviral treatment than direct-acting antivirals (DAAs). To test whether miR-122 levels could be utilized as a biomarker of hepatic adaptive stress response in HCV infection, serum miR-122 level was measured among healthy controls, and chronic HCV patients with or without cirrhosis. Our data show that serum miR-122 expression level remained undetectable in most of the patients with cirrhosis (stage IV fibrosis), suggesting that the pro-survival UPR signaling increases the risk of HCC through STAT3-mediated suppression of miR-122. In conclusion, our data indicate that hepatic pro-survival UPR signaling suppresses the liver-specific HNF4A and its downstream target miR-122 in cirrhosis. These results provide an explanation as to why cirrhosis is a risk factor for the development of HCC in chronic HCV infection.

Dataset Information

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

Publications

IFN-λ Inhibits MiR-122 Transcription through a Stat3-HNF4α Inflammatory Feedback Loop in an IFN-α Resistant HCV Cell Culture System.

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