Alternative titles; symbols
HGNC Approved Gene Symbol: IL22RA2
Cytogenetic location: 6q23.3 Genomic coordinates (GRCh38) : 6:137,143,820-137,173,644 (from NCBI)
IL22RA2 encodes a soluble class II cytokine receptor and naturally occurring IL22 (605330) antagonist (Xu et al., 2001).
By DNA database screening for sequences with homology to the extracellular domain of IL10RB and analysis of 6q24 BAC clone, Dumoutier et al. (2001) identified a cDNA encoding IL22BP, which they designated CRF2X. Sequence analysis predicted that the 231-amino acid protein, approximately 33% identical to the extracellular domains of IL20RA (605620) and IL22R, contains a signal peptide, 4 cysteines conserved among members of the class II cytokine receptor family, and 5 potential N-linked glycosylation sites, but lacks a transmembrane domain. RT-PCR analysis detected expression in breast, lungs, and intestinal tract, with lower levels in skin, testis, brain, heart, and thymus. ELISA showed that IL22BP does indeed bind IL22. Functional and luciferase reporter analysis indicated that IL22BP specifically blocked IL22-induced STAT3 (102582) activation in an intestinal epithelial cell line.
Using similar methods, Kotenko et al. (2001) also cloned and characterized IL22BP, which they initially designated CRF2-10. Western blot analysis showed expression of a 34- to 35-kD glycosylated secreted protein. Crosslinking and autoradiographic analysis confirmed the interaction of IL22 and IL22BP. Functional analysis indicated that IL22BP inhibited IL22-mediated MHC class I antigen expression. EMSA analysis demonstrated inhibition of STAT1 (600555) and STAT3 DNA-binding complexes. Northern blot analysis showed blocking of SOCS3 (604176) expression.
Xu et al. (2001) obtained a cDNA encoding IL22BP, which they termed IL22RA2. They noted the presence of 2 cytokine-binding fibronectin type III domains. IL22RA2 effectively inhibited proliferation of a mouse pre-B cell line in response to IL22. Northern blot analysis revealed expression of 1.6- and 3.0-kb transcripts in placenta and spleen, but not in other tissues. RT-PCR analysis extended the range of tissues expressing IL22RA2 to skin and lung, with lower levels in heart, pancreas, and prostate, as well as the digestive and female reproductive systems. In situ hybridization analysis demonstrated expression in monocytes, activated B cells, and epithelium. Xu et al. (2001) concluded that IL22RA2 may be important as an IL22 antagonist in the regulation of inflammatory responses.
By genomic sequence and RT-PCR analysis, Dumoutier et al. (2001), Kotenko et al. (2001) and Xu et al. (2001) determined that the IL22BP gene contains 6 exons. Xu et al. (2001) determined that the IL22BP gene spans about 29 kb of genomic DNA.
Huber et al. (2012) described the crucial role of IL22BP in controlling tumorigenesis and epithelial cell proliferation in the colon. IL22BP is highly expressed by dendritic cells in the colon in steady-state conditions. Sensing of intestinal tissue damage via the NLRP3 (606416) or NLRP6 (609650) inflammasomes led to an IL18 (600953)-dependent downregulation of IL22BP, thereby increasing the ratio of IL22/IL22BP. IL22, which is induced during intestinal tissue damage, exerted protective properties during the peak of damage, but promoted tumor development if uncontrolled during the recovery phase. Thus, the IL22-IL22BP axis critically regulates intestinal tissue repair and tumorigenesis in the colon.
By BAC analysis, Dumoutier et al. (2001) and Kotenko et al. (2001) mapped the IL22BP gene to chromosome 6q24.1-q25.2, in the vicinity of IFNGR1, in a head-to-tail orientation. By radiation hybrid analysis, Xu et al. (2001) localized the gene to chromosome 6q23.3-q24.2.
Dumoutier, L., Lejeune, D., Colau, D., Renauld, J. C. Cloning and characterization of IL-22 binding protein, a natural antagonist of IL-10-related T cell-derived inducible factor/IL 22. J. Immun. 166: 7090-7095, 2001. [PubMed: 11390453] [Full Text: https://doi.org/10.4049/jimmunol.166.12.7090]
Huber, S., Gagliani, N., Zenewicz, L. A., Huber, F. J., Bosurgi, L., Hu, B., Hedl, M., Zhang, W., O'Connor, W., Jr., Murphy, A. J., Valenzuela, D. M., Yancopoulos, G. D., Booth, C. J., Cho, J. H., Ouyang, W., Abraham, C., Flavell, R. A. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491: 259-263, 2012. [PubMed: 23075849] [Full Text: https://doi.org/10.1038/nature11535]
Kotenko, S. V., Izotova, L. S., Mirochnitchenko, O. V., Esterova, E., Dickensheets, H., Donnelly, R. P., Pestka, S. Identification, cloning, and characterization of a novel soluble receptor that binds IL-22 and neutralizes its activity. J. Immun. 166: 7096-7103, 2001. [PubMed: 11390454] [Full Text: https://doi.org/10.4049/jimmunol.166.12.7096]
Xu, W., Presnell, S. R., Parrish-Novak, J., Kindsvogel, W., Jaspers, S., Chen, Z., Dillon, SR., Gao, Z., Gilbert, T., Madden, K., Schlutsmeyer, S., Yao, L., and 11 others. A soluble class II cytokine receptor, IL-22RA2, is a naturally occurring IL-22 antagonist. Proc. Nat. Acad. Sci. 98: 9511-9516, 2001. [PubMed: 11481447] [Full Text: https://doi.org/10.1073/pnas.171303198]