Alternative titles; symbols
HGNC Approved Gene Symbol: IL10RB
Cytogenetic location: 21q22.11 Genomic coordinates (GRCh38): 21:33,266,367-33,310,182 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 21q22.11 | {Hepatitis B virus, susceptibility to} | 610424 | 3 | |
| Inflammatory bowel disease 25, early onset, autosomal recessive | 612567 | Autosomal recessive | 3 |
Class II cytokine receptor family (CRF2) members, such as IL10RB, are characterized by the presence of an extracellular domain composed of 2 subdomains of 100 amino acids.
Lutfalla et al. (1993) cloned a full-length cDNA corresponding to a gene mapping to the D21S58 locus. The encoded protein, called CRF2-4, was shown to be a typical class II member of the cytokine receptor family.
Gibbs and Pennica (1997) also cloned IL10RB by exon trapping of YAC clones spanning the interferon receptor region. The IL10RB cDNA encodes a 325-amino acid protein. Northern blot analysis revealed expression of a 2.0-kb transcript in all tissues tested except brain. Gibbs and Pennica (1997) used the human sequence to obtain the mouse cDNA.
Lutfalla et al. (1993) determined that the IL10RB gene, which they called CRFB4, spans more than 30 kb. Its intron/exon structure is conserved with all other members of the cytokine receptor family.
By pulsed field mapping, Lutfalla et al. (1993) showed that the physical distance between the IL10RB gene and IFNAR1 (107450) on chromosome 21 is less than 35 kb. Cheng et al. (1993) demonstrated that the murine homologs of the IL10RB, IFNAR1, and GART (138440) genes are closely situated on chromosome 16.
Kotenko et al. (1997) noted that interleukin-10 (IL10; 124092) binds to a CRF2 family member, IL10RA (146933), but fails to induce signal transduction. Gel shift analysis showed that coexpression of IL10RA with IL10RB renders cells sensitive to IL10. SDS-PAGE analysis indicated that both receptors and IL10 coimmunoprecipitate.
Sheppard et al. (2003) showed that IL10RB is part of a heterodimeric class II cytokine receptor with IL28RA (607404) that enhances signaling and antiviral activity in response to IL28A (607401), IL28B (607402), and IL29 (607403).
Based on phylogenetic analysis, Sheikh et al. (2004) hypothesized that IL10RB and either IL20RA (605620) or IL22RA1 (605457) form the heterodimer that serves as the IL26 (605679) receptor. Both IL20RA and IL22RA1 activate STAT3 (102582) upon ligand binding, but in conjunction with a chimeric IFNGR1 (107470) intracellular chain, they activate STAT1 (600555). EMSA analysis demonstrated that IL26 induced STAT1 activation in transfected cell lines expressing IL10RB and IL20RA/IFNGR1 chimeras, but not in cell lines expressing IL10RB and IL22RA1/IFNGR1 chimeras. In the absence of the IFNGR1 intracellular chain, STAT3 was activated predominantly. STAT1 activation was inhibited in the presence of antibodies to IL10RB, IL20RA, or IL26. ELISA and chromatographic analysis indicated that IL26 interacted predominantly with IL20RA. Sheikh et al. (2004) showed that IL20RA has a restricted tissue distribution, in contrast with the ubiquitous expression of IL10RB. IL26 stimulation of a colorectal adenocarcinoma cell line expressing IL10RB and IL20RA consistently induced stronger activation of STAT3 than STAT1. Sheikh et al. (2004) concluded that the receptor combination of IL10RB and IL20RA is unique and specific for IL26.
By microsatellite analysis of Gambian families, Frodsham et al. (2006) identified a class II cytokine receptor gene cluster on chromosome 21q22 as a major susceptibility locus for hepatitis B virus (HBV; see 610424) persistence. They found that coding SNPs in 2 genes within this cluster, phe8 to ser (F8S; 602376.0001) in IFNAR2 (602376) and lys47 to glu (K47E; 123889.0001) in IL10RB, were associated, both independently and as a haplotype, with a higher risk of HBV persistence. In both cases, the more common variant (F8 and K47, respectively) was associated with HBV persistence. There was no significant difference in RNA expression of the F8 and S8 IFNAR2 variants, but FACS analysis demonstrated higher cell surface expression of the F8 variant. Furthermore, signal transduction assays showed increased MHC class I expression in response to IFNA (147660) in F8-expressing cells compared with S8-expressing cells, as well as greater protection from encephalomyocarditis virus challenge in F8-expressing cells. The E47 variant of IL10RB showed higher RNA and cell surface expression than the K47 variant. Moreover, E47-expressing cells were better able to inhibit TNF (191160) release after lipopolysaccharide challenge compared with K47-expressing cells.
In a consanguineous Turkish family with early-onset severe enterocolitis mapping to chromosome 21q (IBD25; 612567), Glocker et al. (2009) sequenced the candidate gene IL10RB and identified homozygosity for a mutation in 2 affected sibs (W159X; 123889.0002). Glocker et al. (2009) analyzed the IL10RB gene in 90 patients with adult-onset IBD, 45 with Crohn disease and 45 with ulcerative colitis, but found no mutations or other sequence variations; 32 children with onset of IBD at more than 12 months of age and 6 additional patients with onset of disease within the first year of life were also negative for mutations in IL10RB, although 1 of the latter patients had a missense mutation in the IL10RA gene (146933.0002), which encodes the protein with which IL10R2 forms the heterotetrameric IL10 receptor. Analysis of W159X-mutant cells showed increased secretion of TNF and other proinflammatory cytokines compared to controls, and the secretion of TNF by mutant cells was not reduced by administration of IL10, suggesting that IL10-dependent 'negative feedback' regulation is disrupted in these cells.
In a French boy with early-onset inflammatory bowel disease in whom hematopoietic cells showed a lack of response to IL10, Begue et al. (2011) identified homozygosity for a nonsense mutation in the IL10RB gene (123889.0003).
By generating mice with an inactivated IL10RB gene, Spencer et al. (1998) demonstrated that responses to IFNA1 and IFNG (147570) are unimpaired but that cells from these mice are unable to respond to IL10. Although various other immune system markers and functions were similar to those of wildtype mice, histopathologic analysis showed that IL10RB -/- mice develop splenomegaly and colitis.
Frodsham et al. (2006) found that SNPs in the IFNAR2 (602376) and IL10RB genes resulting in phe8-to-ser (F8S; 602376.0001) and lys47-to-glu (K47E) changes, respectively, were associated, both independently and as a haplotype, with a higher risk of hepatitis B virus (HBV; see 610424) persistence. In both cases, the more common variant (F8 and K47, respectively) was associated with HBV persistence.
In a brother and sister with early-onset severe enterocolitis (IBD25; 612567) from a consanguineous Turkish family, Glocker et al. (2009) identified homozygosity for a 477G-A transition in exon 4 of the IL10RB gene, resulting in a trp159-to-ter (W159X) substitution. The unaffected parents and 2 unaffected sibs were heterozygous for the mutation, which was not found in 180 German controls, 70 Turkish controls, or 30 Iranian controls. Functional analysis revealed that the mutation abrogated IL10-induced signaling, as shown by deficient STAT3 (102582) phosphorylation on stimulation with IL10. In addition, peripheral blood mononuclear cells from the mutation-positive brother showed increased secretion of TNF and other proinflammatory cytokines compared to controls, and the secretion of TNF by mutant cells was not reduced by administration of IL10, suggesting that IL10-dependent 'negative feedback' regulation is disrupted in these cells.
In a French boy with early-onset inflammatory bowel disease (IBD25; 612567), Begue et al. (2011) identified homozygosity for a 421G-T transversion in exon 3 of the IL10RB gene, resulting in a glu141-to-ter (E141X) substitution. His healthy parents and brother were heterozygous for the mutation. The patient's hematopoietic cells showed a lack of response to IL10 (124092), and ileal tissue did not respond to stimulation with IL22 (605330). Histologic examination of intestinal tissue showed typical epithelioid cell granulomas, and RT-PCR showed massively increased levels of proinflammatory cytokines; however, mRNA transcripts of IL22-inducible proteins were almost absent in this patient, suggesting a defective response to IL22.
Begue, B., Verdier, J., Rieux-Laucat, F., Goulet, O., Morali, A., Canioni, D., Hugot, J.-P., Daussy, C., Verkarre, V., Pigneur, B., Fischer, A., Klein, C., Cerf-Bensussan, N., Ruemmele, F. M. Defective IL10 signaling defining a subgroup of patients with inflammatory bowel disease. Am. J. Gastroent. 106: 1544-1555, 2011. [PubMed: 21519361] [Full Text: https://doi.org/10.1038/ajg.2011.112]
Cheng, S., Lutfalla, G., Uze, G., Chumakov, I. M., Gardiner, K. GART, SON, IFNAR, and CRF2-4 genes cluster on human chromosome 21 and mouse chromosome 16. Mammalian Genome 4: 338-342, 1993. [PubMed: 8318737] [Full Text: https://doi.org/10.1007/BF00357094]
Frodsham, A. J., Zhang, L., Dumpis, U., Taib, N. A. M., Best, S., Durham, A., Hennig, B. J. W., Hellier, S., Knapp, S., Wright, M., Chiaramonte, M., Bell, J. I., Graves, M., Whittle, H. C., Thomas, H. C., Thursz, M. R., Hill, A. V. S. Class II cytokine receptor gene cluster is a major locus for hepatitis B persistence. Proc. Nat. Acad. Sci. 103: 9148-9153, 2006. [PubMed: 16757563] [Full Text: https://doi.org/10.1073/pnas.0602800103]
Gibbs, V. C., Pennica, D. CRF2-4: isolation of cDNA clones encoding the human and mouse proteins. Gene 186: 97-101, 1997. [PubMed: 9047351] [Full Text: https://doi.org/10.1016/s0378-1119(96)00690-7]
Glocker, E.-O., Kotlarz, D., Boztug, K., Gertz, E. M., Schaffer, A. A., Noyan, F., Perro, M., Diestelhorst, J., Allroth, A., Murugan, D., Hatscher, N., Pfeifer, D., and 16 others. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. New Eng. J. Med. 361: 2033-2045, 2009. [PubMed: 19890111] [Full Text: https://doi.org/10.1056/NEJMoa0907206]
Kotenko, S. V., Krause, C. D., Izotova, L. S., Pollack, B. P., Wu, W., Pestka, S. Identification and functional characterization of a second chain of the interleukin-10 receptor complex. EMBO J. 16: 5894-5903, 1997. [PubMed: 9312047] [Full Text: https://doi.org/10.1093/emboj/16.19.5894]
Lutfalla, G., Gardiner, K., Uze, G. A new member of the cytokine receptor gene family maps on chromosome 21 at less than 35 kb from IFNAR. Genomics 16: 366-373, 1993. [PubMed: 8314576] [Full Text: https://doi.org/10.1006/geno.1993.1199]
Sheikh, F., Baurin, V. V., Lewis-Antes, A., Shah, N. K., Smirnov, S. V., Anantha, S., Dickensheets, H., Dumoutier, L., Renauld, J.-C., Zdanov, A., Donnelly, R. P., Kotenko, S. V. Cutting edge: IL-26 signals through a novel receptor complex composed of IL-20 receptor 1 and IL-10 receptor 2. J. Immun. 172: 2006-2010, 2004. [PubMed: 14764663] [Full Text: https://doi.org/10.4049/jimmunol.172.4.2006]
Sheppard, P., Kindsvogel, W., Xu, W., Henderson, K., Schlutsmeyer, S., Whitmore, T. E., Kuestner, R., Garrigues, U., Birks, C., Roraback, J., Ostrander, C., Dong, D., and 14 others. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nature Immun. 4: 63-68, 2003. [PubMed: 12469119] [Full Text: https://doi.org/10.1038/ni873]
Spencer, S. D., Di Marco, F., Hooley, J., Pitts-Meek, S., Bauer, M., Ryan, A. M., Sordat, B., Gibbs, V. C., Aguet, M. The orphan receptor CRF2-4 is an essential subunit of the interleukin 10 receptor. J. Exp. Med. 187: 571-578, 1998. [PubMed: 9463407] [Full Text: https://doi.org/10.1084/jem.187.4.571]