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IL-29 is the dominant type III interferon produced by hepatocytes during acute hepatitis C virus infection.

ABSTRACT: UNLABELLED:Early, vigorous intrahepatic induction of interferon (IFN)-stimulated gene (ISG) induction is a feature of hepatitis C virus (HCV) infection, even though HCV inhibits the induction of type I IFNs in vitro. To identify the cytokines and cells that drive ISG induction and mediate antiviral activity during acute HCV infection, type I and III IFN responses were studied in (1) serial liver biopsies and plasma samples obtained from 6 chimpanzees throughout acute HCV infection and (2) primary human hepatocyte (PHH) cultures upon HCV infection. Type I IFNs were minimally induced at the messenger RNA (mRNA) level in the liver and were undetectable at the protein level in plasma during acute HCV infection of chimpanzees. In contrast, type III IFNs, in particular, interleukin (IL)-29 mRNA and protein, were strongly induced and these levels correlated with ISG expression and viremia. However, there was no association between intrahepatic or peripheral type III IFN levels and the outcome of acute HCV infection. Infection of PHH with HCV recapitulated strong type III and weak type I IFN responses. Supernatants from HCV-infected PHH cultures mediated antiviral activity upon transfer to HCV-replicon-containing cells. This effect was significantly reduced by neutralization of type III IFNs and less by neutralization of type I IFNs. Furthermore, IL-29 production by HCV-infected PHH occurred independently from type I IFN signaling and was not enhanced by the presence of plasmacytoid dendritic cells. CONCLUSION:Hepatocyte-derived type III IFNs contribute to ISG induction and antiviral activity, but are not the principal determinant of the outcome of HCV infection.

SUBMITTER: Park H

PROVIDER: S-EPMC3581145 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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IL-29 is the dominant type III interferon produced by hepatocytes during acute hepatitis C virus infection.

Park Heiyoung H Serti Elisavet E Eke Onyinyechi O Muchmore Brian B Prokunina-Olsson Ludmila L Capone Stefania S Folgori Antonella A Rehermann Barbara B

Hepatology (Baltimore, Md.) 20121119 6

<h4>Unlabelled</h4>Early, vigorous intrahepatic induction of interferon (IFN)-stimulated gene (ISG) induction is a feature of hepatitis C virus (HCV) infection, even though HCV inhibits the induction of type I IFNs in vitro. To identify the cytokines and cells that drive ISG induction and mediate antiviral activity during acute HCV infection, type I and III IFN responses were studied in (1) serial liver biopsies and plasma samples obtained from 6 chimpanzees throughout acute HCV infection and (2 ...[more]

PMID: 22706965

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Project description:Background & aimsInterleukin (IL)-20 and IL-22 belong to the IL-10 family. IL-10 is a well-documented anti-inflammatory cytokine while IL-22 is well known for epithelial protection and its antibacterial function, showing great therapeutic potential for organ damage; however, the function of IL-20 remains largely unknown.MethodsIl20 knockout (Il20-/-) mice and wild-type littermates were generated and injected with Concanavalin A (ConA) and Klebsiella pneumoniae (K.P.) to induce acute hepatitis and bacterial infection, respectively.ResultsIl20-/- mice were resistant to acute hepatitis and exhibited selectively elevated levels of the hepatoprotective cytokine IL-6. Such selective inhibition of IL-6 by IL-20 was due to IL-20 targeting hepatocytes that produce high levels of IL-6 but a limited number of other cytokines. Mechanistically, IL-20 upregulated NAD(P)H: quinone oxidoreductase 1 (NQO1) expression and subsequently promoted the protein degradation of transcription factor IκBζ, resulting in selective downregulation of the IκBζ-dependent gene Il6 as well several other IκBζ-dependent genes including lipocalin-2 (Lcn2). Given the important role of IL-6 and LCN2 in limiting bacterial infection, we examined the effect of IL-20 on bacterial infection and found Il20-/- mice were resistant to K.P. infection and exhibited elevated levels of hepatic IκBζ-dependent antibacterial genes. Moreover, IL-20 upregulated hepatic NQO1 by binding to IL-22R1/IL-20R2 and activating ERK/p38MAPK/NRF2 signaling pathways. Finally, the levels of hepatic IL1B, IL20, and IκBζ target genes were elevated, and correlated with each other, in patients with severe alcoholic hepatitis.ConclusionsIL-20 selectively inhibits hepatic IL-6 production rather than exerting IL-10-like broad anti-inflammatory properties. Unlike IL-22, IL-20 aggravates acute hepatitis and bacterial infection. Thus, anti-IL-20 therapy could be a promising option to control acute hepatitis and bacterial infection.Lay summarySeveral interleukin (IL)-20 family cytokines have been shown to play important roles in controllimg inflammatory responses, infection and tissue damage, but the role of IL-20 remains unclear. Herein, we elucidated the role of IL-20 in liver disease and bacterial infection. We show that IL-20 can aggravate hepatitis and bacterial infection; thus, targeting IL-20 holds promise for the treatment of patients with liver disease.

Project description:Background & aimsHepatitis C virus (HCV) is difficult to eradicate and type III interferons (IFN-?, composed of IL-28A, IL-28B and IL-29) are novel therapeutic candidates. We hypothesized that IFN-? have immunomodulatory effects in HCV- infected individuals.Materials and methodsWe analyzed the expression of IFN-? and its receptor (composed of IL-10R2 and IFN-?R subunits) in the blood and livers of patients with chronic (c)HCV infection compared to controls (those who cleared HCV by sustained virological response, SVR, and those with liver inflammation of non-viral origin, non-alcoholic steatohepatitis, NASH). We also compared the proliferative capacity of dendritic cells (DCs) obtained from healthy individuals and those with chronic HCV using a mixed leukocyte reaction combined with 3H-Td incorporation. In addition, the composition of the IFN-? receptor (IFN-?R) on myeloid DCs, plasmacytoid DCs, PBMCs, and T cells was determined by FACS analysis.ResultsWe report that the expression of IFN-? protein in serum and mRNA in liver is increased in cHCV patients, but not in those with HCV SVR or NASH, compared to controls. Liver level of IFN-?R mirrored the expression of serum IFN-? and was higher in cHCV, compared to controls and HCV-SVR patients, suggesting that elevation of IFN-? and IFN-?R are HCV-dependent. We further identified that innate immune cell populations expressed complete IFN-? receptor. In vitro, recombinant IFN-? promoted differentiation of monocyte-derived dendritic cells (DCs) into a phenotype with low T cell stimulatory capacity and high PD-L1 expression, which further promoted expansion of existing regulatory T cells. IFN-?-DCs failed to induce de novo generation of regulatory T cells. The inhibitory capacity of IFN-?-DCs was counteracted by recombinant IL-12 and by neutralization of the PD-1/PD-L1 system.ConclusionsOur novel findings of the immunomodulatory effect of IFN-? contribute to the understanding of the anti-inflammatory and/or anti-viral potential of IFN-? in cHCV.

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IL-29 is the dominant type III interferon produced by hepatocytes during acute hepatitis C virus infection.

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IL-29 is the dominant type III interferon produced by hepatocytes during acute hepatitis C virus infection.

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