Interleukin-26: an IL-10-related cytokine produced by Th17 cells - PubMed (original) (raw)

Review

Raymond P Donnelly et al. Cytokine Growth Factor Rev. 2010 Oct.

Abstract

IL-26 is classified as a member of the IL-10 cytokine family because it has limited sequence homology to IL-10 and the IL-10-related cytokines. The human IL-26 gene, IL26, is located on chromosome 12q15 between the genes for two other important class-2 cytokines, IFNG (IFN-γ) and IL22 (IL-22). IL-26 is often co-expressed with IL-22 by activated T cells, especially Th17 cells. It signals through a heterodimeric receptor complex composed of the IL-20R1 and IL-10R2 chains. IL-26 receptors are primarily expressed on non-hematopoietic cell types, particularly epithelial cells. Signaling through IL-26 receptor complexes results in the activation of STAT1 and STAT3 with subsequent induction of IL-26-responsive genes. The biological functions of IL-26 have only begun to be defined.

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Figures

Figure 1

Figure 1

A schematic comparison showing syntenic conservation of the IFN-γ, IL-26 and IL-22 loci in the human (Homo sapiens) and murine (Mus musculus) genomes. Information regarding the IFN-γ/IL-26/IL-22 locus was obtained from the NCBI map viewer for human chromosome-12 and murine chromosome-10. The closed boxes and arrowheads denote the positions and transcriptional orientations of the genes. The murine IL-26 gene fragments are shown as “open” boxes because they represent a bioinformatic prediction of an incomplete IL-26 gene. Abbreviations used: IFN-γ, interferon gamma; MDM, mouse double minute; IL, interleukin; ψ, pseudogene.

Figure 2

Figure 2

A comparison of the deduced amino acid sequences for the IL-26 gene in several mammalian and lower vertebrate species. Residues conserved across the sequences of multiple species are shaded. Dashes (−) indicate gaps that were introduced for optimal alignment. Multiple sequence alignment was carried out using Bio-edit software which uses Clustal W [version 1.8] and BLOSUM series was used for Protein weight matrix. The accession numbers for sequences used in this analysis are as follows: human, Homo sapiens, GenBank accession no. EAW97181; bovine, Bos taurus, GenBank accession no. XP_001250652; chimpanzee, Pan troglodytes, XP_001152032; rhesus monkey, Macaca mulatta, GenBank accession no. XP_001117154; zebrafish, Danio rerio, GenBank accession no. AAI63119; western clawed frog, Xenopus tropicalis, GenBank accession no. ABU54058.

Figure 3

Figure 3

The IL-26 receptor complex. A. The IL-26 receptor complex is composed of two polypeptide chains: the ligand-binding chain, IL-20R1, and the accessory receptor chain, IL-10R2. IL-26 binds initially to IL-20R1, and then rapidly recruits the IL-10R2 chain to complete assembly of the active receptor complex. Ligand-induced heterodimerization of these receptor chains initiates a signal transduction cascade that results in the activation and nuclear translocation of STAT1 and STAT3. IL-20R1 can also dimerize with another class II cytokine receptor, IL-20R2, to generate receptors for IL-19, IL-20 and IL-24. B. IL-26 induces tyrosine phosphorylation of STAT1 and STAT3 in the human colorectal carcinoma cell line, COLO 205. COLO 205 cells were incubated with IL-22 or IL-26 (100 ng/mL) in the presence or absence of recombinant human IL-22 binding protein (IL-22BP) for 30 minutes at 37°C. At the end of this incubation period, whole cell lysates were prepared and analyzed by western blotting with antibodies specific for tyrosine-phosphorylated STAT1 or tyrosine-phosphorylated-STAT3 and total STAT1 and total STAT3.

Figure 3

Figure 3

The IL-26 receptor complex. A. The IL-26 receptor complex is composed of two polypeptide chains: the ligand-binding chain, IL-20R1, and the accessory receptor chain, IL-10R2. IL-26 binds initially to IL-20R1, and then rapidly recruits the IL-10R2 chain to complete assembly of the active receptor complex. Ligand-induced heterodimerization of these receptor chains initiates a signal transduction cascade that results in the activation and nuclear translocation of STAT1 and STAT3. IL-20R1 can also dimerize with another class II cytokine receptor, IL-20R2, to generate receptors for IL-19, IL-20 and IL-24. B. IL-26 induces tyrosine phosphorylation of STAT1 and STAT3 in the human colorectal carcinoma cell line, COLO 205. COLO 205 cells were incubated with IL-22 or IL-26 (100 ng/mL) in the presence or absence of recombinant human IL-22 binding protein (IL-22BP) for 30 minutes at 37°C. At the end of this incubation period, whole cell lysates were prepared and analyzed by western blotting with antibodies specific for tyrosine-phosphorylated STAT1 or tyrosine-phosphorylated-STAT3 and total STAT1 and total STAT3.

Figure 4

Figure 4

A structure-based sequence alignment of human IL-26 (A.) and a model of the human IL-26/IL-20R1/IL-10R2 ternary complex structure (B.). The sequence alignment was performed as described in the text. The six main helices (A–F) are denoted in Fig. 4A, and * and #s represent putative IL-20R1 and IL-10R2 binding residues, respectively. In the structure shown in Fig. 4B, helices A and B are colored red and purple, respectively. Cysteine residues are shown in yellow to denote residues that are conserved in the IL-19 sequence and green for residues that are not. The putative position of the cell membrane is shown at the bottom of the figure.

Figure 5

Figure 5

The IL-20R1 gene, IL20RA, encodes several RNA splice variants. Three variants of the IL-20R1 gene can be expressed in cells that express this receptor chain. The first is the full-length 3.6 kb transcript (GenBank accession no. NM_014432) that encodes the complete receptor polypeptide, including both fibronectin type-III (FnIII) domains of the extracellular region. The second is a 1.7 kb variant (GenBank accession no. AY358883) that lacks the membrane-distal FnIII domain, but retains the membrane-proximal FnIII domain, the trans-membrane domain, and the complete intracellular region. This variant arises as a result of deletion of most of exon 1 and all of exon 3. The third transcript is a 1.9 kb variant (GenBank accession no. AK098312) that lacks the entire extracellular region, but retains a small part of the trans-membrane domain and the complete intracellular domain. This variant arises as a result of the complete deletion of exons 1, 2 and 3. Although the full-length (3.6 kb) transcript encodes a functional IL-26-binding protein, the functions of the shorter 1.7 kb and 1.9 kb variants are unknown.

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