The expanded family of class II cytokines that share the IL-10 receptor-2 (IL-10R2) chain

Division of Therapeutic Proteins, HFM-538, 1401 Rockville Pike, Rockville, MD 20852, USA.
Journal of Leukocyte Biology (Impact Factor: 4.29). 09/2004; 76(2):314-21. DOI: 10.1189/jlb.0204117
Source: PubMed

ABSTRACT Several novel interleukin (IL)-10-related cytokines have recently been discovered. These include IL-22, IL-26, and the interferon-lambda (IFN-lambda) proteins IFN-lambda1 (IL-29), IFN-lambda2 (IL-28A), and IFN-lambda3 (IL-28B). The ligand-binding chains for IL-22, IL-26, and IFN-lambda are distinct from that used by IL-10; however, all of these cytokines use a common second chain, IL-10 receptor-2 (IL-10R2; CRF2-4), to assemble their active receptor complexes. Thus, IL-10R2 is a shared component in at least four distinct class II cytokine-receptor complexes. IL-10 binds to IL-10R1; IL-22 binds to IL-22R1; IL-26 binds to IL-20R1; and IFN-lambda binds to IFN-lambdaR1 (also known as IL-28R). The binding of these ligands to their respective R1 chains induces a conformational change that enables IL-10R2 to interact with the newly formed ligand-receptor complexes. This in turn activates a signal-transduction cascade that results in rapid activation of several transcription factors, particularly signal transducer and activator of transcription (STAT)3 and to a lesser degree, STAT1. Activation by IL-10, IL-22, IL-26, or IFN-lambda can be blocked with neutralizing antibodies to the IL-10R2 chain. Although IL-10R2 is broadly expressed on a wide variety of tissues, only a subset of these tissues expresses the ligand-binding R1 chains. The receptors for these cytokines are often present on cell lines derived from various tumors, including liver, colorectal, and pancreatic carcinomas. Consequently, the receptors for these cytokines may provide novel targets for inhibiting the growth of certain types of cancer.

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    • "IFN-as and IFN-b bind to the ubiquitously expressed IFN-a receptor. IFN-ks bind a different receptor, consisting of the ubiquitously expressed IL-10R2 chain (shared with the IL-10 receptor) and a unique IFN-k receptor 1 chain whose expression is mainly restricted to epithelial cells [20] [21]. Off note, IFN-k receptor 1 expression is very low in control liver biopsy samples , but significantly increased in the setting of chronic viral infections [22]. "
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    ABSTRACT: Hepatitis C virus has been identified a quarter of a decade ago as a leading cause of chronic viral hepatitis that can lead to cirrhosis and hepatocellular carcinoma. Only a minority of patients can clear the virus spontaneously during acute infection. Elimination of HCV during acute infection correlates with a rapid induction of innate, especially interferon (IFN) induced genes, and a delayed induction of adaptive immune responses. However, the majority of patients is unable to clear the virus and develops viral persistence in face of an ongoing innate and adaptive immune response. The virus has developed several strategies to escape these immune responses. For example, to escape innate immunity, the HCV NS3/4A protease can efficiently cleave and inactivate two important signalling molecules in the sensory pathways that react to HCV pathogen-associated molecular patterns (PAMPs) to induce IFNs, i.e., the mitochondrial anti-viral signalling protein (MAVS) and the Toll-IL-1 receptor-domain-containing adaptor-inducing IFN-β (TRIF). Despite these escape mechanisms, IFN-stimulated genes (ISGs) are induced in a large proportion of patients with chronic infection. Of note, chronically HCV infected patients with constitutive IFN-stimulated gene (ISG) expression have a poor response to treatment with pegylated IFN-α (PegIFN-α) and ribavirin. The mechanisms that protect HCV from IFN-mediated innate immune reactions are not entirely understood, but might involve blockade of ISG protein translation at the ribosome, localization of viral replication to cell compartments that are not accessible to anti-viral IFN-stimulated effector systems, or direct antagonism of effector systems by viral proteins. Escape from adaptive immune responses can be achieved by emergence of viral escape mutations that avoid recognition by antibodies and T cells. In addition, chronic infection is characterized by the presence of functionally and phenotypically altered NK and T cell responses that are unable to clear the virus but most likely contribute to the ongoing liver disease. In this review, we will summarize current knowledge about the role of innate and adaptive immune responses in determining the outcome of HCV infection.
    Journal of Hepatology 11/2014; 61(1). DOI:10.1016/j.jhep.2014.06.035 · 11.34 Impact Factor
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    • "Additionally, IL-26 activated the mitogen-activated protein (MAP) kinases extracellular-signal-regulated kinase-1/2 (ERK-1/2) and stress-activated protein kinase/c-Jun N-terminal kinase-1/2 (SAPK/JNK), as well as Akt phosphorylation [34]. Experience from different laboratories showed that the IL-26 response of the cell line HT-29 is variable, since forced expression of IL-20R1 was necessary for IL-26-dependent STAT3 phosphorylation in several approaches [1,29,34]. Both, IL-26 and IL-22, act on epithelial cells and induce similar target genes in Colo-205 cells, such as SOCS3 [19,34]. "
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    ABSTRACT: Interleukin-26 (IL-26) belongs to the IL-10 cytokine family, is produced by activated T cells, and targets epithelial target cells for signal transduction. Here, we describe the IL-26 effects on the infection of culture cells with recombinant vesicular stomatitis virus (VSV), human cytomegalovirus (HCMV), and herpes simplex virus type 1 (HSV-1) expressing green fluorescent protein. After pre-incubation with recombinant IL-26 and at low multiplicity of infection, VSV showed strongly enhanced infection and replication rates as measured for infectivity, for transcript levels, and for protein expression. Control proteins did not affect VSV infection. The IL-26 effect was independent of the IL-26 receptor and neutralized by anti-IL-26 serum. Pre-incubation of VSV was much more efficient than pre-incubation of the target cells to enhance virus infection. IL-26 increased virus adsorption to target cells as shown by quantitative reverse-transcription PCR. In contrast, the infection of IL-26-treated human fibroblasts with HCMV was inhibited and the infection by HSV-1 was not altered by IL-26. Thus, IL-26 differentially modulates the infection by different enveloped viruses.
    PLoS ONE 07/2013; 8(7):e70281. DOI:10.1371/journal.pone.0070281 · 3.23 Impact Factor
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    • "IL10RB, originally known as orphan interferon receptor family member CRFB4/CRF2-4, is the accessory subunit of the IL10 receptor complex (IL10R) 26. For IL10 to transduce signals into a cell, the ligand-binding chain of the IL-10R, IL10RA, is required 26, 27. IL10 signaling is an anti-inflammatory pathway that, through IL10R, inhibits cytokine production by T cells and natural killer (NK) cells, and suppresses antigen presenting cells (APC) cytokine expression 28. "
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    ABSTRACT: Human endometase/matrilysin-2/matrix metalloproteinase-26 (MMP-26) is an endopeptidase mostly produced by human carcinoma cells. While MMPs are thought to regulate the dynamics of extracellular matrix turnover, new evidence shows that these enzymes may play a critical regulatory role in inflammation. To investigate the role of MMP-26 in inflammation, three different variants of androgen repressed human prostate cancer (ARCaP) cells were investigated in the study: parental, MMP-26 sense cDNA-transfected, and MMP-26 antisense cDNA-transfected ARCaP cells. Protein lysates and RNA from control and genetically modified cells were analyzed by Western blotting and real-time reverse transcription polymerase chain reaction on arrays of genes critical to the inflammatory response. In comparison to parental controls, up-regulation of MMP-26 expression in MMP-26 sense cDNA-transfected cells resulted in a decrease in inflammatory genes expression. Conversely, inflammatory genes were up-regulated in MMP-26 antisense cDNA-transfected cells. Therefore, modulation of MMP-26 levels significantly affects the expression of inflammatory genes, suggesting an anti-inflammatory role of MMP-26. To determine a possible mechanism of action, further analysis, at both transcript and protein levels, revealed a dramatic down-regulation of interleukin-10 receptor B (IL10RB) in MMP-26 antisense cDNA-transfected cells. The low level of IL10RB was inversely correlated with matrix metalloproteinase-9 (MMP-9) expression. Collectively, our data suggest that the deficiency of MMP-26 may promote inflammation via inhibition of IL10RB-mediated signaling. These results propose a novel anti-inflammation function of MMP-26 and could provide novel molecular insight of therapeutic targeting.
    Journal of Cancer 03/2013; 4(4):296-303. DOI:10.7150/jca.5788 · 3.27 Impact Factor
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