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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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          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 references60

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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.

                Author and article information

                Role: Editor
                PLoS Pathog
                PLoS Pathogens
                Public Library of Science (San Francisco, USA )
                March 2008
                March 2008
                14 March 2008
                : 4
                : 3
                : e1000017
                [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.

                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.
                : 14 September 2007
                : 30 January 2008
                Page count
                Pages: 12
                Research Article
                Immunology/Innate Immunity
                Virology/Animal Models of Infection
                Virology/Host Antiviral Responses

                Infectious disease & Microbiology
                Infectious disease & Microbiology


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