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

Emmanuel Thomas, Veronica D. Gonzalez, Qisheng Li, Ankit A. Modi, Weiping Chen, Mazen Noureddin, Yaron Rotman, T. Jake Liang

Research output: Contribution to journalArticle

194 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)978-988
Number of pages11
JournalGastroenterology
Volume142
Issue number4
DOIs
StatePublished - Apr 1 2012
Externally publishedYes

Fingerprint

Virus Diseases
Innate Immunity
Hepacivirus
Interferons
Liver
Genes
Interferon Type I
Pan troglodytes
Interleukins
Hepatocytes
Up-Regulation
Interferon Regulatory Factor-3
Biopsy
Gene Expression
Chemokines
Antiviral Agents
Hepatocellular Carcinoma
Cell Line
Messenger RNA

Keywords

  • Cytokine
  • IL29
  • IRF
  • Nonresponder

ASJC Scopus subject areas

  • Gastroenterology

Cite this

HCV infection induces a unique hepatic innate immune response associated with robust production of type III interferons. / Thomas, Emmanuel; Gonzalez, Veronica D.; Li, Qisheng; Modi, Ankit A.; Chen, Weiping; Noureddin, Mazen; Rotman, Yaron; Liang, T. Jake.

In: Gastroenterology, Vol. 142, No. 4, 01.04.2012, p. 978-988.

Research output: Contribution to journalArticle

Thomas, Emmanuel ; Gonzalez, Veronica D. ; Li, Qisheng ; Modi, Ankit A. ; Chen, Weiping ; Noureddin, Mazen ; Rotman, Yaron ; Liang, T. Jake. / HCV infection induces a unique hepatic innate immune response associated with robust production of type III interferons. In: Gastroenterology. 2012 ; Vol. 142, No. 4. pp. 978-988.
@article{644f531b1e9c4de4b7d5960e11883ac3,
title = "HCV infection induces a unique hepatic innate immune response associated with robust production of type III interferons",
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.",
keywords = "Cytokine, IL29, IRF, Nonresponder",
author = "Emmanuel Thomas and Gonzalez, {Veronica D.} and Qisheng Li and Modi, {Ankit A.} and Weiping Chen and Mazen Noureddin and Yaron Rotman and Liang, {T. Jake}",
year = "2012",
month = "4",
day = "1",
doi = "10.1053/j.gastro.2011.12.055",
language = "English",
volume = "142",
pages = "978--988",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "4",

}

TY - JOUR

T1 - HCV infection induces a unique hepatic innate immune response associated with robust production of type III interferons

AU - Thomas, Emmanuel

AU - Gonzalez, Veronica D.

AU - Li, Qisheng

AU - Modi, Ankit A.

AU - Chen, Weiping

AU - Noureddin, Mazen

AU - Rotman, Yaron

AU - Liang, T. Jake

PY - 2012/4/1

Y1 - 2012/4/1

N2 - 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.

AB - 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.

KW - Cytokine

KW - IL29

KW - IRF

KW - Nonresponder

UR - http://www.scopus.com/inward/record.url?scp=84862777861&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84862777861&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2011.12.055

DO - 10.1053/j.gastro.2011.12.055

M3 - Article

VL - 142

SP - 978

EP - 988

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 4

ER -