Interferon-lambda: a new addition to an old family

Abstract

The discovery and initial description of the interferon-lambda (IFN-lambda) family in early 2003 opened an exciting new chapter in the field of IFN research. There are 3 IFN-lambda genes that encode 3 distinct but highly related proteins denoted IFN-lambda1, -lambda2, and -lambda3. These proteins are also known as interleukin-29 (IL-29), IL-28A, and IL-28B, respectively. Collectively, these 3 cytokines comprise the type III subset of IFNs. They are distinct from both type I and type II IFNs for a number of reasons, including the fact that they signal through a heterodimeric receptor complex that is different from the receptors used by type I or type II IFNs. Although type I IFNs (IFN-alpha/beta) and type III IFNs (IFN-lambda) signal via distinct receptor complexes, they activate the same intracellular signaling pathway and many of the same biological activities, including antiviral activity, in a wide variety of target cells. Consistent with their antiviral activity, expression of the IFN-lambda genes and their corresponding proteins is inducible by infection with many types of viruses. Therefore, expression of the type III IFNs (IFN-lambdas) and their primary biological activity are very similar to the type I IFNs. However, unlike IFN-alpha receptors which are broadly expressed on most cell types, including leukocytes, IFN-lambda receptors are largely restricted to cells of epithelial origin. The potential clinical importance of IFN-lambda as a novel antiviral therapeutic agent is already apparent. In addition, preclinical studies by several groups indicate that IFN-lambda may also be useful as a potential therapeutic agent for other clinical indications, including certain types of cancer.

FIG. 1.

A phylogenetic alignment of the class II cytokine family genes. Alignment of the human interferon-λ (IFN-λ) genes with either (A) the human type I IFN genes or (B) the human interleukin-10 (IL-10)-related cytokines was used to generate a phylogenetic tree for the class II cytokine genes. Only one IFN-α was used in this alignment because the thirteen human IFN-α subtypes have nearly identical sequences. Because of the low sequence identity, these trees are subject to small changes, so these alignments are intended to be instructive, not definitive.

FIG. 2.

Organization of the genes encoding the IFN-λs and their receptors. Schematic representations of the chromosomal regions of the human and mouse genomes that encode the IFN-λ (A) and IFN-λ receptor (B and C) genes. The genes are transcribed in the direction indicated by the arrows. Although the human and murine IFN-λ and IFN-λ receptor loci are colinear, the human genome encodes 3 functional IFN-λ genes and 1 pseudogene (denoted IFN-λ4Ψ), whereas there are only 2 functional IFN-λ coding genes in the murine genome: Il28a (IFN-λ2) and Il28b (IFN-λ3). mIFN-λ1Ψ and mIFN-λ4Ψ genes are pseudogenes. Unspliced transcripts (right panel for the IFN-λ genes, and bottom panel for the IFN-λ receptor genes) are schematically shown as strings of filled or open boxes (exons) joined by intervening lines (introns). Spliced transcripts are also shown as shaded/open boxes with vertical lines indicating the relative positions of former introns. The coding regions of exons are shaded and the segments corresponding to the 5' and 3' untranslated regions are open (not shaded).

FIG. 3.

A model of the IFN-λ receptor signaling pathway. The type I, type II, and type III IFNs bind to distinct receptor complexes on the cell membrane. Signal transduction activated by the binding of IFNs to their cognate receptors induces expression of many IFN-stimulated genes (ISGs). The proteins encoded by these genes in turn mediate the antiviral activity of the IFNs, particularly the type I and III IFNs. The functional IFN-λ receptor complex consists of 2 distinct receptor chains: the ligand-specific IFN-λR1 chain (also known as IL-28RA) and the IL-10R2 chain. The binding of IFN-λ to its receptor induces a signaling cascade that results in the activation of STAT1 and STAT2 which together with IRF-9 (p48) form ISGF3 transcription factor complexes. The newly formed ISGF3 complexes then translocate from the cytosol to the nucleus where they bind to IFN-stimulated response elements (ISRE) in the promoters of ISGs such as IRF7, MX1, and OAS1.