Ile50Val variant of IL4Rα upregulates IgE synthesis and associates with atopic asthma

Mitsuyasu, Hiromichi; Izuhara, Kenji; Mao, Xiao-Quan; Gao, Peisong; Arinobu, Yojiro; Enomoto, Tadao; Kawai, Mitsuru; Sasaki, Sei; Dake, Yoshihiro; Hamasaki, Naotaka; Shirakawa, Taro; Hopkin, Julian M.

doi:10.1038/472

Cited by 339 publications

(269 citation statements)

References 15 publications

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“…Some of these polymorphisms significantly upregulate receptor response to IL-4, with a resultant increased activation of STAT6, and thus increased cell proliferation and IgE production. 17,19 Ober et al 18 have also reported an apparent haplotype effect in outbred populations. S411L (+1232 C4T) and S761P (+2281 T4C) are further single nucleotide polymorphisms (SNPs) in exon 12, but have largely been excluded from previous analyses due to low minor allele frequencies and, therefore, low statistical power.…”

Section: Introductionmentioning

confidence: 95%

“…Variations in the ligands of IL4Ra, IL-4 and IL-13, have been associated with atopic phenotypes. 15,16 Polymorphisms in IL4RA have also been reported to be associated with atopic phenotypes: the I50V (+148 A4T), C406R (+1216 T4C), S478P (+1682 T4C, previously S503P), and Q551R (+1902 G4T, previously R576Q) variants have shown association with increased risk for asthma 17,18 and atopy. 18,19 All polymorphisms except for +148 A4T, which is in exon 5, are located in exon 12.…”

Section: Introductionmentioning

confidence: 98%

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Testing the possible negative association of type 1 diabetes and atopic disease by analysis of the interleukin 4 receptor gene

et al. 2003

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Variations in the interleukin 4 receptor A (IL4RA) gene have been reported to be associated with atopy, asthma, and allergy, which may occur less frequently in subjects with type 1 diabetes (T1D). Since atopy shows a humoral immune reactivity pattern, and T1D results from a cellular (T lymphocyte) response, we hypothesised that alleles predisposing to atopy could be protective for T1D and transmitted less often than the expected 50% from heterozygous parents to offspring with T1D. We genotyped seven exonic single nucleotide polymorphisms (SNPs) and the -3223 C4T SNP in the putative promoter region of IL4RA in up to 3475 T1D families, including 1244 Finnish T1D families. Only the À3223 C4T SNP showed evidence of negative association (P ¼ 0.014). There was some evidence for an interaction between À3233 C4T and the T1D locus IDDM2 in the insulin gene region (P ¼ 0.001 in the combined and P ¼ 0.02 in the Finnish data set). We, therefore, cannot rule out a genetic effect of IL4RA in T1D, but it is not a major one.

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Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 98%

Testing the possible negative association of type 1 diabetes and atopic disease by analysis of the interleukin 4 receptor gene

et al. 2003

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“…IL-4 is a mast cell growth factor (10), and has been shown to induce Fc⑀RI expression on developing human mast cells (11)(12). These activities, coupled with the linkage of IL-4 receptor polymorphisms to allergic disease (13,14), argue for the proatopic nature of IL-4. However, our recent data demonstrating that IL-4 inhibits Fc⑀RI and Kit expression (15, 16) supports a homeostatic role for IL-4 in allergy.…”

Section: Il-10 Inhibits Fc⑀ri Expression In Mouse Mastmentioning

confidence: 99%

IL-10 Inhibits FcεRI Expression in Mouse Mast Cells

Gillespie

DeMartino

Zhu

et al. 2004

The Journal of Immunology

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FcεRI expression and function is a central aspect of allergic disease. Using bone marrow-derived mouse mast cell populations, we have previously shown that the Th2 cytokine IL-4 inhibits FcεRI expression and function. In the current study we show that the Th2 cytokine IL-10 has similar regulatory properties, and that it augments the inhibitory effects of IL-4. FcεRI down-regulation was functionally significant, as it diminished inflammatory cytokine production and IgE-mediated FcεRI up-regulation. IL-10 and IL-4 reduced FcεRI β protein expression without altering the α or γ subunits. The ability of IL-4 and IL-10 to alter FcεRI expression by targeting the β-chain, a critical receptor subunit known to modulate receptor expression and signaling, suggests the presence of a Th2 cytokine-mediated homeostatic network that could serve to both initiate and limit mast cell effector function.

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“…Eight missense and six silent polymorphisms have been described [11][12][13]. Some of the polymorphisms have been reported to be associated with IgE-mediated disorders [12][13][14]. Although the evidence for association is preliminary and contradictory results exist [15,16], those findings are of interest, as the reported single-nucleotide polymorphisms (SNPs) may change the function of the molecule.…”

Section: Introductionmentioning

confidence: 99%

“…Although the evidence for association is preliminary and contradictory results exist [15,16], those findings are of interest, as the reported single-nucleotide polymorphisms (SNPs) may change the function of the molecule. The amino acid change from valine to isoleucine in position 50, which was associated with atopic asthma in the Japanese population, upregulated the receptor response to IL4 when transfected into both mouse and human cell lines [14]. The 576R allele, which has been reported to be associated with atopy and hyper-IgE syndrome, was also associated with higher levels of expression of the low-affinity receptor for IgE (CD23) than the wild type allele after IL4 induction [12].…”

Section: Introductionmentioning

confidence: 99%

A Second-Generation Association Study of the 5q31 Cytokine Gene Cluster and the Interleukin-4 Receptor in Asthma

et al. 2001

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We have analyzed a dense set of single-nucleotide polymorphisms (SNPs) and microsatellites spanning the T-helper cytokine gene cluster (interleukins 3, 4, 5, 9, and 13, interferon regulatory factor-1, colony-stimulating factor-2, and T-cell transcription factor-7) on 5q31 and the gene encoding the interleukin-4 receptor (IL4R) on 16p12 among Finnish families with asthma. As shown by haplotype pattern mining analysis, the number of disease-associated haplotype patterns differed from that expected for the 129Q allele polymorphism in IL13 for high serum total immunoglobulin (Ig) E levels, but not for asthma. The same SNP also yielded the best haplotype associations. For IL4R, asthma-associated haplotype patterns, most spanning the S411L polymorphism, showed suggestive association. However, these haplotypes consisted of the major alleles for the intracellular part of the receptor and were very common among both patients and controls. The minor alleles 503P and 576R have been reported to be associated with decreased serum IgE levels and changes in the biological activity of the protein, especially when inherited together. In the Finnish population, these two polymorphisms segregated in strong linkage disequilibrium. Our data support previous findings regarding IL4R, indicating that 503P and 576R may act as minor protecting alleles for IgE-mediated disorders.Key Words: asthma, atopy, haplotype pattern mining, polymorphism, association families). The study showed suggestive linkage for asthma (LOD = 2.6) but no evidence for atopy [8]. Although it is not known whether human genes in the 5q31 cytokine cluster are genetic regulators for atopic disorders, experimental models of asthma have shown the importance of both IL4 and IL13 signaling. Administration of either exogenous IL4 or IL13 induced the asthma phenotype in mice [9]. However, neither of these cytokines was able to induce the asthma phenotype in mice deficient in the IL4 receptor (IL4R) [9]. The IL4 receptor is a heterodimer consisting of a common ␥-chain that is shared by several other interleukin receptors (IL2, IL7, IL9, and IL13) and a ligand-specific ␣-chain encoded by IL4R. An IL4R␣-IL13R␣ heterodimer is also able to transduce IL13 signaling [10] and is an important signaling pathway in the asthma model. All this indicates the importance of IL4R␣ in IL4/IL13-mediated signaling.

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Ile50Val variant of IL4Rα upregulates IgE synthesis and associates with atopic asthma

Cited by 339 publications

References 15 publications

Testing the possible negative association of type 1 diabetes and atopic disease by analysis of the interleukin 4 receptor gene

Testing the possible negative association of type 1 diabetes and atopic disease by analysis of the interleukin 4 receptor gene

IL-10 Inhibits FcεRI Expression in Mouse Mast Cells

A Second-Generation Association Study of the 5q31 Cytokine Gene Cluster and the Interleukin-4 Receptor in Asthma

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