IL-4 regulates Bim expression and promotes B cell maturation in synergy with BAFF conferring resistance to cell death at negative selection checkpoints.

Autor:	Granato A; Department of Immunology, Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro 21941-590, Brazil., Hayashi EA; Department of Immunology, Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro 21941-590, Brazil., Baptista BJ; Department of Immunology, Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro 21941-590, Brazil., Bellio M; Department of Immunology, Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro 21941-590, Brazil., Nobrega A; Department of Immunology, Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro 21941-590, Brazil afnobrega@gmail.com.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2014 Jun 15; Vol. 192 (12), pp. 5761-75. Date of Electronic Publication: 2014 May 16.
DOI:	10.4049/jimmunol.1300749
Abstrakt:	IL-4 plays an essential role in the activation of mature B cells, but less is known about the role of IL-4 in B cell maturation and tolerance checkpoints. In this study, we analyzed the effect of IL-4 on in vitro B cell maturation, from immature to transitional stages, and its influence on BCR-mediated negative selection. Starting either from purified CD19(+)IgM(-) B cell precursors, or sorted bone marrow immature (B220(low)IgM(low)CD23(-)) and transitional (B220(int)IgM(high)CD23(-)) B cells from C57BL/6 mice, we compared the maturation effects of IL-4 and BAFF. We found that IL-4 stimulated the generation of CD23(+) transitional B cells from CD23(-) B cells, and this effect was comparable to BAFF. IL-4 showed a unique protective effect against anti-IgM apoptotic signals on transitional B cell checkpoint, not observed with BAFF. IL-4 and BAFF strongly synergized to promote B cell maturation, and IL-4 also rendered it refractory to BCR-mediated cell death. IL-4 blocked upregulation of proapoptotic Bim protein levels induced by BCR crosslinking, suggesting that diminished levels of intracellular Bim promote protection to BCR-induced cell death. Evidence was obtained indicating that downmodulation of Bim by IL-4 occurred in a posttranscriptional manner. Consistent with data obtained in vitro, IL-4 in vivo was able to inhibit Bim upregulation and prevent cell death. These results contribute to the understanding of the role of IL-4 in B lymphocyte physiology, unveiling a previously undescribed activity of this cytokine on the maturation of B cells, which could have important implications on the breaking of B cell central tolerance in autoimmunity. (Copyright © 2014 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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