Alternative titles; symbols
HGNC Approved Gene Symbol: IL13RA1
Cytogenetic location: Xq24 Genomic coordinates (GRCh38): X:118,727,606-118,805,228 (from NCBI)
Hilton et al. (1996) cloned murine NR4, a previously unrecognized receptor identified on the basis of sequence similarity with members of the hemopoietin receptor family. By using transient expression of the mouse NR4 in COS-7 cells, they found that NR4 encodes the IL13 receptor alpha-chain, a low-affinity receptor capable of binding IL13 (147683) but not IL4 (147780) or interleukins 2, 7, 9, or 15. The NR4 cDNA was predicted to encode a protein of 424 amino acid residues, containing a putative signal sequence and transmembrane domain.
Aman et al. (1996) cloned cDNAs corresponding to the human IL13R-alpha chain (see also IL13RA2; 300130). The protein had 76% homology to murine IL13R-alpha, with 95% amino acid identity in the cytoplasmic domain.
IL4 and IL13 are 2 cytokines that are secreted by activated T cells and have similar effects on monocytes and B cells. Zurawski et al. (1993) demonstrated that the IL4 receptor (147781) is a complex of at least 2 components. They described a mutant form of human IL4 that competitively antagonizes both human IL4 and human IL13. The amino acid sequences of IL4 and IL13 are approximately 30% homologous, and circular dichroism spectroscopy demonstrates that both proteins have a highly alpha-helical structure. IL13 competitively inhibited binding of IL4 to functional human IL4 receptors expressed on a cell line that responds to both IL4 and IL13. The binding of IL4 to an IL4-responsive cell line that does not respond to IL13, and the binding of IL4 to cloned IL4R ligand binding protein expressed on heterologous cells, were not inhibited by IL13. The results demonstrated that IL4 and IL13 share a receptor component that is important for signal transduction. Hilton et al. (1996) reviewed these and other data suggesting a model of IL4 and IL13 receptor composition and function.
Hilton et al. (1996) showed that stable expression of NR4 in the cytotoxic T-cell line CTLL2 resulted in the generation of high-affinity IL13 receptors capable of transducing a proliferative signal in response to IL13 and, moreover, led to competitive cross-reactivity in the binding of IL4 and IL13. These results suggested to the authors that the IL13 receptor alpha-chain (NR4) is a primary binding subunit of the IL13 receptor and may also be a component of IL4 receptors.
Only weak IL13 binding activity was found by Aman et al. (1996) in cells transfected with only IL13R-alpha; however, the combination of both IL13R-alpha and IL4R-alpha resulted in substantial binding activity, indicating that both chains are essential components of the IL13 receptor. Whereas IL13R-alpha served as an alternative accessory protein to the common cytokine receptor gamma chain for IL4 signaling, it could not replace the function of gamma(c) (IL2RG; 308380) in allowing enhanced IL2 binding activity. Nevertheless, the overall size and length of the cytoplasmic domain of IL13R-alpha and gamma(c) are similar, and like gamma(c), the IL13R-alpha gene (IL13RA) is located on the X chromosome.
Because IL4 and IL13 and their specific signaling pathways are considered attractive targets for the treatment of allergy and asthma, Kelly-Welch et al. (2003) reviewed the signaling connections of these cytokines. IL4 interacts with IL4R with high affinity, leading to dimerization with either the common gamma chain (IL2RG), a component of receptors for a number of cytokines, to create a type I receptor, or with IL13RA1 to form a type II receptor. IL13, on the other hand, binds with high affinity to IL13RA1, which induces heterodimerization with IL4R to form a complex identical to the type II receptor. Alternatively, IL13 may bind with even greater affinity to IL13RA2, which fails to induce a signal, indicating that it acts as a decoy receptor. The C-terminal tails of the IL4 and IL13 receptor subunits interact with tyrosine kinases of the Janus kinase family (e.g., JAK1; 147795), leading to interaction with STAT6 (601512), which binds to consensus sequences in the promoters of IL4- and IL13-regulated genes. Kelly-Welch et al. (2003) proposed that subtle differences in IL4 and IL13 signaling due to polymorphisms near docking sites in IL4R may have profound implications for allergy and asthma.
Using RT-PCR and flow cytometric analysis, Myrtek et al. (2004) demonstrated that IL13 and IL4 have inhibitory effects on IL13RA1 expression on eosinophils, while IFNG (147570), TNFA (191160), and, particularly, TGFB (190180) enhance IL13RA1 expression. The positive regulatory responses evoked by TGFB and IFNG did not, however, prevent the inhibitory effects of IL13. Myrtek et al. (2004) concluded that there is a cytokine regulatory network influencing the reactivity of eosinophils to IL13.
LaPorte et al. (2008) reported the crystal structures of the complete set of IL4 and IL13 type I (IL4RA/IL2RG/IL4) and type II (IL4RA/IL13RA1/IL4 and IL4RA/IL13RA1/IL13) ternary signaling complexes at the 3.0-angstrom level. They noted that the type I receptor complex is more active in regulating Th2 development, whereas the type II receptor complex is not found on T cells and is more active in regulating cells that mediate airway hypersensitivity and mucus secretion. The type I complex revealed a structural basis for the ability of IL2RG to recognize 6 different IL2RG cytokines.
Aman et al. (1996) demonstrated the X-linkage of IL13RA by analysis of a panel of 24 DNA samples from mostly monochromosomal somatic hybrids. An IL13RA-specific band of 148 bp was amplified reproducibly from 2 hybrids, one containing only human chromosome X and the other containing both human chromosomes 1 and X.
Guo et al. (1997) mapped the IL13RA gene to chromosome Xq24 by in situ hybridization. It lies between 2 other cytokine receptor genes: IL2RG on Xq13.1 and the interleukin-9 receptor gene (IL9R; 300007) on Xq28. The lack of nucleotide sequence similarity suggests unrelated evolutionary pathways between these receptor genes.
Heinzmann et al. (2000) determined that R130Q variant of human IL13 (147683.0002), which they referred to as R110Q, associated with asthma in case-control populations from Britain and Japan (peak odds ratio (OR) = 2.31, 95% confidence interval, 1.33 - 4.00); the variant also predicted asthma and higher serum IL13 levels in a general, Japanese pediatric population. A noncoding variant of IL13RA1, 1398A-G, associated primarily with high IgE levels (OR = 3.38 in males, 1.10 in females) rather than asthma.
Aman, M. J., Tayebi, N., Obiri, N. I., Puri, R. K., Modi, W. S., Leonard, W. J. cDNA cloning and characterization of the human interleukin 13 receptor alpha chain. J. Biol. Chem. 271: 29265-29270, 1996. [PubMed: 8910586] [Full Text: https://doi.org/10.1074/jbc.271.46.29265]
Guo, J., Apiou , F., Mellerin, M.-P., Lebeau, B., Jacques, Y., Minvielle, S. Chromosome mapping and expression of the human interleukin-13 receptor. Genomics 42: 141-5, 1997. [PubMed: 9177784] [Full Text: https://doi.org/10.1006/geno.1997.4628]
Heinzmann, H., Mao, X.-Q., Akaiwa, M., Kreomer, R. T., Gao, P.-S., Ohshima, K., Umeshita, R., Abe, Y., Braun, S., Yamashita, T., Roberts, M. H., Sugimoto, R., and 20 others. Genetic variants of IL-13 signalling and human asthma and atopy. Hum. Molec. Genet. 9: 549-559, 2000. [PubMed: 10699178] [Full Text: https://doi.org/10.1093/hmg/9.4.549]
Hilton, D. J., Zhang, J.-G., Metcalf, D., Alexander, W. S., Nicola, N. A., Willson, T. A. Cloning and characterization of a binding subunit of the interleukin 13 receptor that is also a component of the interleukin 4 receptor. Proc. Nat. Acad. Sci. 93: 497-501, 1996. [PubMed: 8552669] [Full Text: https://doi.org/10.1073/pnas.93.1.497]
Kelly-Welch, A. E., Hanson, E. M., Boothby, M. R., Keegan, A. D. Interleukin-4 and interleukin-13 signaling connections maps. Science 300: 1527-1528, 2003. [PubMed: 12791978] [Full Text: https://doi.org/10.1126/science.1085458]
LaPorte, S. L., Juo, Z. S., Vaclavikova, J., Colf, L. A., Qi, X., Heller, N. M., Keegan, A. D., Garcia, K. C. Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13 system. Cell 132: 259-272, 2008. [PubMed: 18243101] [Full Text: https://doi.org/10.1016/j.cell.2007.12.030]
Myrtek, D., Knoll, M., Matthiesen, T., Krause, S., Lohrmann, J., Schillinger, D., Idzko, M., Virchow, J. C., Friedrich, K., Luttmann, W. Expression of interleukin-13 receptor alpha 1-subunit on peripheral blood eosinophils is regulated by cytokines. Immunology 112: 597-604, 2004. [PubMed: 15270731] [Full Text: https://doi.org/10.1046/j.1365-2567.2004.01897.x]
Zurawski, S. M., Vega, F., Jr., Huyghe, B., Zurawski, G. Receptors for interleukin-13 and interleukin-4 are complex and share a novel component that functions in signal transduction. EMBO J. 12: 2663-2670, 1993. [PubMed: 8101483] [Full Text: https://doi.org/10.1002/j.1460-2075.1993.tb05927.x]