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-Mediated Inhibition of Human IgE Synthesis by IL-21 Is Associated with a Polymorphism in the IL-21R Gene1
* Institut National de la Santé et de la Recherche Médicale, Unité 454, and
Service de Chirurgie Digestive, Centre Hospitalier Universitaire St. Eloi, Montpellier, France;
Département de Pharmacologie, Université de Montréal, Montréal, Canada; and
Novartis Institutes for Biomedical Research Vienna, Department of Autoimmune Diseases, Vienna, Austria
IL-21 is a cytokine produced by CD4+ T cells that has been reported to regulate human, as well as, mouse T and NK cell function and to inhibit Ag-induced IgE production by mouse B cells. In the present study, we show that human rIL-21 strongly enhances IgE production by both CD19+CD27– naive, and CD19+CD27+ memory B cells, stimulated with anti-CD40 mAb and rIL-4 and that it promotes the proliferative responses of these cells. However, rIL-21 does not significantly affect anti-CD40 mAb and rIL-4-induced C
promoter activation in a gene reporter assay, nor germline C mRNA expression in purified human spleen or peripheral blood B cells. In contrast, rIL-21 inhibits rIL-4-induced IgE production in cultures of PBMC or total splenocytes by an IFN-
-dependent mechanism. The presence of a polymorphism (T-83C), in donors heterozygous for this mutation was found to be associated not only with lower rIL-21-induced IFN- production levels, but also with a lower sensitivity to the inhibitory effects of IL-21 on the production of IgE, compared with those in donors expressing the wild-type IL-21R. Taken together, these results show that IL-21 differentially regulates IL-4-induced human IgE production, via its growth- and differentiation-promoting capacities on isotype-, including IgE-, committed B cells, as well as via its ability to induce IFN- production, most likely by T and NK cells, whereas the outcome of these IL-21-mediated effects is dependent on the presence of a polymorphism in the IL-21R.
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 L.G. is the recipient of a grant from the Fondation Paul Hamel. This study was supported by MedBioMed (Montpellier, France).
2 Address correspondence and reprint requests to Dr. Hans Yssel, Institut National de la Santé et de la Recherche Médicale, Unité 454, Centre Hospitalier Universitaire Arnaud de Villeneuve, 371, Avenue Doyen Gaston Giraud, 34295 Montpellier, cedex 5, France. E-mail address: yssel{at}montp.inserm.fr
3 Abbreviations used in this paper: CSR, class switch recombination; EFI
, elongation factor I.
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