An Important Role for Type III Interferon (IFN-λ/IL-28) in TLR-Induced Antiviral Activity

Abstract

Type III IFNs (IFN-λ/IL-28/29) are cytokines with type I IFN-like antiviral activities, which remain poorly characterized. We herein show that most cell types expressed both types I and III IFNs after TLR stimulation or virus infection, whereas the ability of cells to respond to IFN-λ was restricted to a narrow subset of cells, including plasmacytoid dendritic cells and epithelial cells. To examine the role of type III IFN in antiviral defense, we generated IL-28Rα-deficient mice. These mice were indistinguishable from wild-type mice with respect to clearance of a panel of different viruses, whereas mice lacking the type I IFN receptor (IFNAR−/−) were significantly impaired. However, the strong antiviral activity evoked by treatment of mice with TLR3 or TLR9 agonists was significantly reduced in both IL-28RA−/− and IFNAR−/− mice. The type I IFN receptor system has been shown to mediate positive feedback on IFN-αβ expression, and we found that the type I IFN receptor system also mediates positive feedback on IFN-λ expression, whereas IL-28Rα signaling does not provide feedback on either type I or type III IFN expression in vivo. Finally, using bone-marrow chimeric mice we showed that TLR-activated antiviral defense requires expression of IL-28Rα only on nonhemopoietic cells. In this compartment, epithelial cells responded to IFN-λ and directly restricted virus replication. Our data suggest type III IFN to target a specific subset of cells and to contribute to the antiviral response evoked by TLRs.

Fish virus-induced interferon exerts antiviral function through Stat1 pathway

“…In the latter case, IRF7 is necessary but, prior to its action, it has to be synthesized through the IFN␤-activated Stat1 pathway (Marie et al, 1998;Sato et al, 2000). IRF3 and IRF7 seem to play similar roles in regulation of type III IFNs (Ank et al, 2008). However, our results showed that both fish IRF3 and IRF7 are induced by virus infection and IFN treatment through the Stat1 pathway, whereas in mammals, IRF3 is constitutively expressed and not induced in virus-infected or IFNtreated cells (Au et al, 1995).…”

“…In mammals, IFN␤ is an early phase IFN and can prime the expression of later phase IFN genes other than itself (Deonarain et al, 2000;Marie et al, 1998;Sato et al, 2000), and IFN␣ cannot be induced by itself (Ank et al, 2006). In contrast, type III IFNs are induced directly by type I IFNs and also themselves (Ank et al, 2008;Ank et al, 2006;Osterlund et al, 2007). Therefore, when auto-regulation is concerned, fish IFN genes resemble more type III than type I IFNs.…”

Hepatitis C pharmacogenetics: State of the art in 2010

“…Lambda IFNs inhibit HCV replication in vitro 16,17 and may protect against other RNA-containing viruses in vivo. 13,18 Lambda IFNs are thought to produce intracellular responses similar to those of IFN-a but are more specific in their tissue targets because of restricted receptor expression. This has led some to hypothesize that lambda IFNs have similar antiviral activity as IFN-a, but with fewer adverse effects.…”

“…16 However, type 1 and type 3 stimulate similar pathways, with receptor binding resulting in phosphorylation of the kinases JAK1 and Tyk2, activation of the transcription factor complex containing STAT1, STAT2, and IFN regulatory factor 9, and up-regulation of a similar set of interferon-stimulated genes (ISGs). 16,18 Improved viral clearance could result from alterations in IL28B expression, messenger RNA splicing, half-life, or cytokine-receptor affinity or specificity. The responder haplotype of rs8099917 has been weakly associated with higher expression levels of IL28A and IL28B in peripheral blood mononuclear cells.…”

Intron-Containing Type I and Type III IFN Coexist in Amphibians: Refuting the Concept That a Retroposition Event Gave Rise to Type I IFNs

“…For example, type I IFNs are able to elicit antiviral responses in all nucleated cells, whereas the type III IFNs are shown to act on a limited number of cell types, such as dendritic and epithelial cells. In addition, it has been suggested that type I and III IFNs could exert their antiviral functions at different stages of infection or against different types of viruses (4,5).…”