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An interleukin-33 gene polymorphism is a modifier for eosinophilia in rats

Genes & Immunity volume 14, pages 192–197 (2013)Cite this article

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Abstract

In previous studies, we identified a loss-of-function mutation in the Cyba gene as the primary cause of hereditary eosinophilia in the Matsumoto Eosinophilia Shinshu (MES) rat strain. We also identified a modifier locus for eosinophilia named eos3 in rats. In this study, we examined the interleukin-33 (Il33) gene as a candidate for the eos3 and found a missense nucleotide substitution in the gene, which resulted in a G171S amino-acid substitution in the IL-33 protein. Recombinant IL-33 isoform with the G171S substitution had approximately 50% of activity of normal isoform in NF-κB-dependent reporter assay, and reduced bioactivity (∼65% of normal) to provoke eosinophilia when injected into mice. In a genetic association study using (ACI × MES) × MES backcross rats, we found that the effects of polymorphic Il33 alleles on blood eosinophil level were manifested only in rats with loss of Cyba function. In these rats, the blood eosinophil level was significantly lower (∼50%) in heterozygotes for the ACI allele of Il33 compared with homozygotes for the MES allele. Oddly, however, eosinophilic MES rats had blood IL-33 content below the detectable limits. These results suggest that the Il33 gene polymorphism could be a modifier of eosinophilia in rats.

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References

  1. Matsumoto K, Matsushita N, Tomozawa H, Tagawa Y . Hematological characteristics of rats spontaneously developing eosinophilia. Exp Anim 2000; 49: 211–215.

    Article  CAS  Google Scholar 

  2. Muto S, Hayashi M, Matsushita N, Momose Y, Shibata N, Umemura T . Systemic and eosinophilic lesions in rats with spontaneous eosinophilia (mes rats). Vet Pathol 2001; 38: 346–350.

    Article  CAS  Google Scholar 

  3. Sano K, Kobayashi M, Sakaguchi N, Ito M, Hotchi M, Matsumoto K . A rat model of hypereosinophilic syndrome. Pathol Int 2001; 51: 82–88.

    Article  CAS  Google Scholar 

  4. Muto S, Kawakubo M, Matsushita N, Maeda N, Momose Y, Matsumoto K . Haematological data for Matsumoto Eosinophilic Shinshu rats as determined by an automated haematology analyzer. Lab Anim 2005; 39: 122–129.

    Article  CAS  Google Scholar 

  5. Muto S, Monnai M, Okuhara Y, Murakami M, Kuroda J, Ono T et al. Altered cytokine expression in mesenteric lymph nodes in a rat strain (Matsumoto Eosinophilic Shinshu) that spontaneously develops hypereosinophilia. Immunology 2005; 116: 373–380.

    Article  CAS  Google Scholar 

  6. Li G, Guo Z, Higuchi K, Kawakubo M, Matsumoto K, Mori M . A locus for eosinophilia in the MES rat is on chromosome 19. Mamm Genome 2005; 16: 516–523.

    Article  CAS  Google Scholar 

  7. Mori M, Li G, Hashimoto M, Nishio A, Tomozawa H, Suzuki N et al. Eosinophilia in the MES rat strain is caused by a loss-of-function mutation in the gene for cytochrome b(-245), alpha polypeptide (Cyba). J Leukoc Biol 2009; 86: 473–478.

    Article  CAS  Google Scholar 

  8. Mori M, Higuchi K, Matsumoto K . A third locus for eosinophilia on chromosome 1 of the MES rats. Exp Anim 2006; 55: 497–500.

    Article  CAS  Google Scholar 

  9. Kurowska-Stolarska M, Hueber A, Stolarski B, McInnes IB . Interleukin-33: a novel mediator with a role in distinct disease pathogenesis. J Intern Med 2010; 269: 29–35.

    Article  Google Scholar 

  10. Miller AM . Role of IL-33 in inflammation disease. J Inflamm 2011; 8: 22.

    Article  CAS  Google Scholar 

  11. Moussion C, Ortega N, Girard JP . The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel ‘alarmin’? PLoS One 2008; 3: e3331.

    Article  Google Scholar 

  12. Lingel A, Weiss TM, Niebuhr M, Pan B, Appleton BA, Wiesmann C et al. Structure of IL-33 and its interaction with the ST2 and IL-1RAcP receptors–insight into heterotrimeric IL-1 signaling complexes. Structure 2009; 17: 1398–1410.

    Article  CAS  Google Scholar 

  13. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 2005; 23: 479–490.

    Article  CAS  Google Scholar 

  14. Chow JYS, Wong CK, Cheung PFY, Lam CKW . Intracellular signaling mechanisms regulating the activation of human eosinophils by the novel Th2 cytokine IL-33: implications for allergic inflammation. Cell Mol Immunol 2010; 7: 26–34.

    Article  CAS  Google Scholar 

  15. Stolarski B, Kurowska-Stolarska M, Kewin P, Xu D, Liew FY . IL-33 exacerbates eosinophil-mediated airway inflammation. J Immunol 2010; 185: 3472–3480.

    Article  CAS  Google Scholar 

  16. Cherry WB, Yoon J, Bartemes KR, Iijima K, Kita H . A novel IL-1 family cytokine, IL-33, potently activates human eosinophils. J Allergy Clin Immunol 2008; 121: 1484–1490.

    Article  CAS  Google Scholar 

  17. Pecaric-Petkovic T, Didichenko SA, Kaempfer S, Spiegl N, Dahinden CA . Human basophils and eosinophils are the direct target leukocytes of the novel IL-1 family member IL-33. Blood 2009; 113: 1526–1534.

    Article  CAS  Google Scholar 

  18. Suzukawa M, Koketsu R, Iikura M, Nakae S, Matsumoto K, Nagase H . Interleukin-33 enhances adhesion, CD11b expression and survival in human eosinophils. Lab Invest 2008; 88: 1245–1253.

    Article  CAS  Google Scholar 

  19. Cayrol C, Girard JP . The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc Natl Acad Sci USA 2009; 106: 9021–9026.

    Article  CAS  Google Scholar 

  20. Matsuba-Kitamura S, Yoshimoto T, Yasuda K, Futatsugi-Yumikura S, Taki Y, Muto T et al. Contribution of IL-33 to induction and augmentation of experimental allergic conjunctivitis. Int Immunol 2010; 22: 479–489.

    Article  CAS  Google Scholar 

  21. Zhiguang X, Wei C, Steven R, Wei D, Rong M, Zhanguo L et al. Over-expression of IL-33 leads to spontaneous pulmonary inflammation in mIL-33 transgenic mice. Immunol Lett 2010; 131: 159–165.

    Article  Google Scholar 

  22. Liu X, Li M, Wu Y, Zhou Y, Zeng L, Huang T . Anti-IL-33 antibody treatment inhibits airway inflammation in a murine model of allergic asthma. Biochem Biophys Res Commun 2009; 386: 181–185.

    Article  CAS  Google Scholar 

  23. Kim YH, Yang TY, Park CS, Ahn SH, Son BK, Kim JH et al. Anti-IL-33 antibody has a therapeutic effect in a murine model of allergic rhinitis. Allergy 2012; 67: 183–190.

    Article  CAS  Google Scholar 

  24. Oboki K, Ohno T, Kajiwara N, Arae K, Morita H, Ishii A et al. IL-33 is a crucial amplifier of innate rather than acquired immunity. Proc Natl Acad Sci USA 2010; 107: 18581–18586.

    Article  CAS  Google Scholar 

  25. Wong CK, Leung KM, Qiu HN, Chow JY, Choi AO, Lam CW . Activation of eosinophils interacting with dermal fibroblasts by pruritogenic cytokine IL-31 and alarmin IL-33: implications in atopic dermatitis. PLoS One 2012; 7: e29815.

    Article  CAS  Google Scholar 

  26. Gudbjartsson DF, Bjornsdottir US, Halapi E, Helgadottir A, Sulem P, Jonsdottir GM et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet 2009; 41: 342–347.

    Article  CAS  Google Scholar 

  27. Buysschaert ID, Grulois V, Eloy P, Jorissen M, Rombaux P, Bertrand B et al. Genetic evidence for a role of IL33 in nasal polyposis. Allergy 2010; 65: 616–622.

    Article  CAS  Google Scholar 

  28. Sakashita M, Yoshimoto T, Hirota T, Harada M, Okubo K, Osawa Y et al. Association of serum interleukin-33 level and the interleukin-33 genetic variant with Japanese cedar pollinosis. Clin Exp Allergy 2008; 38: 1875–1881.

    Article  CAS  Google Scholar 

  29. Lüthi AU, Cullen SP, McNeela EA, Duriez PJ, Afonina IS, Sheridan C et al. Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity 2009; 31: 84–98.

    Article  Google Scholar 

  30. Ali S, Nguyen DQ, Falk W, Martin MU . Caspase 3 inactivates biologically active full length interleukin-33 as a classical cytokine but does not prohibit nuclear translocation. Biochem Biophys Res Commun 2009; 391: 1512–1516.

    Article  Google Scholar 

  31. Kim HR, Jun CD, Lee YJ, Yang SH, Jeong ET, Park SD et al. Levels of circulating IL-33 and eosinophil cationic protein in patients with hypereosinophilia or pulmonary eosinophilia. J Allergy Clin Immunol 2010; 126: 880.e6–882.e6.

    Article  Google Scholar 

  32. Asaka D, Yoshikawa M, Nakayama T, Yoshimura T, Moriyama H, Otori N . Elevated levels of interleukin-33 in the nasal secretions of patients with allergic rhinitis. Int Arch Allergy Immunol 2012; 158 (Suppl 1): 47–50.

    Article  CAS  Google Scholar 

  33. Kearley J, Buckland KF, Mathie SA, Lloyd CM . Resolution of allergic inflammation and airway hyperreactivity is dependent upon disruption of the T1/ST2-IL-33 pathway. Am J Respir Crit Care Med 2009; 179: 772–781.

    Article  CAS  Google Scholar 

  34. Wills-Karp M, Rani R, Dienger K, Lewkowich I, Fox JG, Perkins C et al. Trefoil factor 2 rapidly induces interleukin 33 to promote type 2 immunity during allergic asthma and hookworm infection. J Exp Med 2012; 209: 607–622.

    Article  CAS  Google Scholar 

  35. Yasuda K, Muto T, Kawagoe T, Matsumoto M, Sasaki Y, Matsushita K et al. Contribution of IL-33-activated type II innate lymphoid cells to pulmonary eosinophilia in intestinal nematode-infected mice. Proc Natl Acad Sci USA 2012; 109: 3451–3456.

    Article  CAS  Google Scholar 

  36. Roussel L, Erard M, Cayrol C, Girard J.-P . Molecular mimicry between IL-33 and KSHV for attachment to chromatin through the H2A-H2B acidic pocket. EMBO Rep 2008; 9: 1006–1012.

    Article  CAS  Google Scholar 

  37. Ali S, Mohs A, Thomas M, Klare J, Ross R, Schmitz ML et al. The dual function cytokine IL-33 interacts with the transcription factor NF-κB to dampen NF-κB–stimulated gene transcription. J Immunol 2011; 187: 1609–1616.

    Article  CAS  Google Scholar 

  38. Choi YS, Park JA, Kim J, Rho SS, Park H, Kim YM et al. Nuclear IL-33 is a transcriptional regulator of NF-κB p65 and induces endothelial cell activation. Biochem Biophys Res Commun 2012; 421: 305–311.

    Article  CAS  Google Scholar 

  39. Kang HJ, Lee Y-m, Jeong YJ, Jeong YJ, Park K, Jang M et al. Large-scale preparation of active caspase-3 in E. coli by designing its thrombin-activatable precursors. BMC Biotechnol 2008; 8: 92–99.

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, Matsumoto, Japan

    H Luo, K Higuchi & M Mori

  2. Division of Laboratory Animal Research, Research Center for Human and Environmental Sciences, Shinshu University, Matsumoto, Japan

    K Matsumoto

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  1. H Luo
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  2. K Higuchi
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  3. K Matsumoto
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  4. M Mori
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Correspondence to M Mori.

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Luo, H., Higuchi, K., Matsumoto, K. et al. An interleukin-33 gene polymorphism is a modifier for eosinophilia in rats. Genes Immun 14, 192–197 (2013). https://doi.org/10.1038/gene.2013.7

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