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Gastroenterology. 2012 Apr;142(4):978-88. doi: 10.1053/j.gastro.2011.12.055. Epub 2012 Jan 13.

HCV infection induces a unique hepatic innate immune response associated with robust production of type III interferons.

Author information

1
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health, Bethesda, Maryland 20892, USA.

Abstract

BACKGROUND & AIMS:

Polymorphisms in the IL28B gene have been associated with clearance of hepatitis C virus (HCV), indicating a role for type III interferons (IFNs) in HCV infection. Little is known about the function of type III IFNs in intrinsic antiviral innate immunity.

METHODS:

We used in vivo and in vitro models to characterize the role of the type III IFNs in HCV infection and analyzed gene expression in liver biopsy samples from HCV-infected chimpanzees and patients. Messenger RNA and protein expression were studied in HCV-infected hepatoma cell lines and primary human hepatocytes.

RESULTS:

HCV infection of primary human hepatocytes induced production of chemokines and type III IFNs, including interleukin (IL)-28, and led to expression of IFN-stimulated genes (ISGs). Chimpanzees infected with HCV showed rapid induction of hepatic type III IFN, associated with up-regulation of ISGs and minimal induction of type I IFNs. In liver biopsy specimens from HCV-infected patients, hepatic expression of IL-28 correlated with levels of ISGs but not of type I IFNs. HCV infection produced extensive changes with gene expression in addition to ISGs in primary human hepatocytes. The induction of type III IFNs is regulated by IFN regulatory factor 3 and nuclear factor κB. Type III IFNs up-regulate ISGs with a different kinetic profile than type 1 IFNs and induce a distinct set of genes, which might account for their functional differences.

CONCLUSIONS:

HCV infection results predominantly in induction of type III IFNs in livers of humans and chimpanzees; the level of induction correlates with hepatic levels of ISGs. These findings might account for the association among IL-28, level of ISGs, and recovery from HCV infection and provide a therapeutic strategy for patients who do not respond to IFN therapy.

PMID:
22248663
PMCID:
PMC3435150
DOI:
10.1053/j.gastro.2011.12.055
[Indexed for MEDLINE]
Free PMC Article

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