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PMID:18250457

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Citation

Ank, N, Iversen, MB, Bartholdy, C, Staeheli, P, Hartmann, R, Jensen, UB, Dagnaes-Hansen, F, Thomsen, AR, Chen, Z, Haugen, H, Klucher, K and Paludan, SR (2008) An important role for type III interferon (IFN-lambda/IL-28) in TLR-induced antiviral activity. J. Immunol. 180:2474-85

Abstract

Type III IFNs (IFN-lambda/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-lambda 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-28Ralpha-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-alphabeta expression, and we found that the type I IFN receptor system also mediates positive feedback on IFN-lambda expression, whereas IL-28Ralpha 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-28Ralpha only on nonhemopoietic cells. In this compartment, epithelial cells responded to IFN-lambda 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.

Links

PubMed

Keywords

Animals; Antiviral Agents/metabolism; Antiviral Agents/pharmacology; Crosses, Genetic; Cytokines/biosynthesis; Cytokines/physiology; Epithelial Cells/immunology; Epithelial Cells/metabolism; Female; Hematopoietic Stem Cells/immunology; Hematopoietic Stem Cells/metabolism; Herpes Genitalis/immunology; Herpes Genitalis/metabolism; Herpes Genitalis/prevention & control; Herpesvirus 2, Human/immunology; Ligands; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; Radiation Chimera; Receptors, Cytokine/deficiency; Receptors, Cytokine/genetics; Toll-Like Receptors/metabolism; Toll-Like Receptors/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:INLR1

involved_in

GO:0051607: defense response to virus

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1932389

P

Seeded From UniProt

complete

MOUSE:INLR1

involved_in

GO:0051607: defense response to virus

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2156367

P

Seeded From UniProt

complete

MOUSE:TLR3

involved_in

GO:0051607: defense response to virus

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2429859

P

Seeded From UniProt

complete

MOUSE:TLR9

involved_in

GO:0051607: defense response to virus

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2429859

P

Seeded From UniProt

complete

MOUSE:TLR3

acts_upstream_of_or_within

GO:0051607: defense response to virus

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2429859

P

Seeded From UniProt

complete


See also

References

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