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      IFN-Lambda (IFN-λ) Is Expressed in a Tissue-Dependent Fashion and Primarily Acts on Epithelial Cells In Vivo

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          Abstract

          Interferons (IFN) exert antiviral, immunomodulatory and cytostatic activities. IFN-α/β (type I IFN) and IFN-λ (type III IFN) bind distinct receptors, but regulate similar sets of genes and exhibit strikingly similar biological activities. We analyzed to what extent the IFN-α/β and IFN-λ systems overlap in vivo in terms of expression and response. We observed a certain degree of tissue specificity in the production of IFN-λ. In the brain, IFN-α/β was readily produced after infection with various RNA viruses, whereas expression of IFN-λ was low in this organ. In the liver, virus infection induced the expression of both IFN-α/β and IFN-λ genes. Plasmid electrotransfer-mediated in vivo expression of individual IFN genes allowed the tissue and cell specificities of the responses to systemic IFN-α/β and IFN-λ to be compared. The response to IFN-λ correlated with expression of the α subunit of the IFN-λ receptor (IL-28Rα). The IFN-λ response was prominent in the stomach, intestine and lungs, but very low in the central nervous system and spleen. At the cellular level, the response to IFN-λ in kidney and brain was restricted to epithelial cells. In contrast, the response to IFN-α/β was observed in various cell types in these organs, and was most prominent in endothelial cells. Thus, the IFN-λ system probably evolved to specifically protect epithelia. IFN-λ might contribute to the prevention of viral invasion through skin and mucosal surfaces.

          Author Summary

          Virus-infected cells can secrete interferons (IFNs), cytokines that induce an infection-resistant state in neighboring cells. IFNs are critical to slow down early multiplication of pathogens in the body. Two IFN families exhibiting strikingly similar properties were described: type I IFNs (or IFN-α/β) and type III IFNs (or IFN-λ). Our work addressed the question of the redundancy of these two IFN systems in vivo. First, we found that the relative expression of IFN-λ over that of IFN-α/β exhibited some extent of tissue specificity and was low in the brain. Next, we used a strategy based on in vivo expression of cloned IFN genes to compare the responses of different tissues to IFN-α and IFN-λ. As was suggested by previous in vitro work, response to IFN-λ appeared to be restricted to epithelial cells, unlike response to IFN-α which occurred in most cell types. Tissues with a high epithelial content such as intestine, skin or lungs were the most responsive to IFN-λ and expressed the higher amounts of IFN-λ receptor. Our data suggest that the IFN-λ system evolved as a specific protection of epithelia and that it might contribute to prevent viral invasion through skin and mucosal surfaces.

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          Most cited references 60

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          Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.

          A new method of total RNA isolation by a single extraction with an acid guanidinium thiocyanate-phenol-chloroform mixture is described. The method provides a pure preparation of undegraded RNA in high yield and can be completed within 4 h. It is particularly useful for processing large numbers of samples and for isolation of RNA from minute quantities of cells or tissue samples.
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            IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex.

            We report here the identification of a ligand-receptor system that, upon engagement, leads to the establishment of an antiviral state. Three closely positioned genes on human chromosome 19 encode distinct but paralogous proteins, which we designate interferon-lambda1 (IFN-lambda1), IFN-lambda2 and IFN-lambda3 (tentatively designated as IL-29, IL-28A and IL-28B, respectively, by HUGO). The expression of IFN-lambda mRNAs was inducible by viral infection in several cell lines. We identified a distinct receptor complex that is utilized by all three IFN-lambda proteins for signaling and is composed of two subunits, a receptor designated CRF2-12 (also designated as IFN-lambdaR1) and a second subunit, CRF2-4 (also known as IL-10R2). Both receptor chains are constitutively expressed on a wide variety of human cell lines and tissues and signal through the Jak-STAT (Janus kinases-signal transducers and activators of transcription) pathway. This receptor-ligand system may contribute to antiviral or other defenses by a mechanism similar to, but independent of, type I IFNs.
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              IL-28, IL-29 and their class II cytokine receptor IL-28R.

              Cytokines play a critical role in modulating the innate and adaptive immune systems. Here, we have identified from the human genomic sequence a family of three cytokines, designated interleukin 28A (IL-28A), IL-28B and IL-29, that are distantly related to type I interferons (IFNs) and the IL-10 family. We found that like type I IFNs, IL-28 and IL-29 were induced by viral infection and showed antiviral activity. However, IL-28 and IL-29 interacted with a heterodimeric class II cytokine receptor that consisted of IL-10 receptor beta (IL-10Rbeta) and an orphan class II receptor chain, designated IL-28Ralpha. This newly described cytokine family may serve as an alternative to type I IFNs in providing immunity to viral infection.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                plos
                plpa
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                1553-7366
                1553-7374
                March 2008
                March 2008
                14 March 2008
                : 4
                : 3
                Affiliations
                [1 ]Université catholique de Louvain, de Duve Institute, MIPA-VIRO 74-49, Brussels, Belgium
                [2 ]Department of Virology, University of Freiburg, Freiburg, Germany
                University of California Irvine, United States of America
                Author notes

                Conceived and designed the experiments: CS SP TM. Performed the experiments: CS SP PS TM. Analyzed the data: CS SP TM. Contributed reagents/materials/analysis tools: PS. Wrote the paper: CS SP PS TM. Performed and designed the experiments to define tissues and cells responding to IFNs: CS. Performed and designed the experiments destined to analyze IFN production: SP. Provided Mx-positive mice as well as antibodies, and performed the LACV infections: PS. Helped in the design and performance of several experiments, and wrote the manuscript with the help of all co-authors: TM.

                Article
                07-PLPA-RA-0633R2
                10.1371/journal.ppat.1000017
                2265414
                18369468
                01f49ef3-4a6a-4ce9-bb0f-49125dfab9a3
                Sommereyns et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 12
                Categories
                Research Article
                Immunology/Innate Immunity
                Virology/Animal Models of Infection
                Virology/Host Antiviral Responses

                Infectious disease & Microbiology

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