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* Department of Microbiology, and
Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kamikyo, Kyoto, Japan;
Center for Molecular Biology and Genetics, Kyoto University, Shogoin-Kawahara, Sakyo, Kyoto, Japan; and
Department of Molecular Genetics, School of Medicine, University of Fukui, Shimoaizuki, Matsuoka, Fukui, Japan
IL-21 exerts pleiotrophic immunomodulatory activities on a variety of target cells including B cells that undergo class switch recombination (CSR) to IgE. In this study, we examined whether IgE-mediated systemic anaphylaxis was controlled by in vivo administration of IL-21 using the peanut allergy model in mice and investigated the molecular mechanisms underlying the IL-21-induced regulation of IgE. The anaphylactic reaction was completely abolished by the administration of recombinant mouse IL-21 or an IL-21 expression plasmid in terms of the change of body temperature and anaphylactic symptoms. The recombinant mouse IL-21 treatment remarkably suppressed IgE CSR in splenic B cells, resulting in significant decrease in serum concentrations of total as well as allergen-specific IgE. In the meanwhile, IL-21 provoked B cells in normal as well as allergic mice to express the inhibitor of differentiation 2 (Id2) gene that was shown to be crucially involved in the regulation of the activation-induced cytidine deaminase and IgE CSR. Moreover, mice genetically deficient for Id2 were completely unsusceptible to IL-21-induced prevention of IgE CSR and anaphylaxis. The present study strongly suggests that IL-21 is capable of regulating systemic allergic reactions by inducing the transcriptional regulator Id2, and the cytokine may be useful for clinical intervention for allergic diseases including anaphylaxis.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a Grant-in-Aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology.
2 T.K. and Y.H. equally contributed to this study.
3 Address correspondence and reprint requests to Dr. Osam Mazda, Department of Microbiology, Kyoto Prefectural University of Medicine, Kamikyo, Kyoto 602-8566, Japan. E-mail address: mazda{at}koto.kpu-m.ac.jp
4 Abbreviations used in this paper: KO, knockout; CPE, crude peanut extract; CSR, class switch recombination; B
, IgE producing B; Id, inhibitor of differentiation; rmIL, recombinant mouse IL; i.g., intragastric; GLT, germline C transcript; AID, activation-induced cytidine deaminase; WT, wild type; Pax5, paired box protein 5; HLH, helix-loop-helix.
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