Abstract
Interleukin 4 (IL-4) is a critical cytokine implicated with TH2 immune reactions, which are linked to pathologic conditions of allergic diseases. In that context, the initiation of TH2 responses can critically depend on early basophil-derived IL-4 to activate T-cell responses, which then amplify IL-4 secretion. As a pleiotropic cytokine, IL-4 acts on a broad variety of hematopoietic and non-hematopoietic cells. However, the effect of IL-4 on basophils themselves, which are emerging as relevant players in allergic as well as autoimmune diseases, was only scarcely addressed so far. Here we used in vitro-differentiated mouse basophils to investigate the direct effects of IL-4 on cellular viability and surface expression of the high-affinity receptor for IgE, FcεRI. We observed that IL-4 elicits pronounced pro-survival signaling in basophils, delaying spontaneous apoptosis in vitro to a degree comparable to the known pro-survival effects of IL-3. Our data indicate that IL-4-mediated survival depends on PI3K/AKT signaling and—in contrast to IL-3—seems to be largely independent of transcriptional changes but effectuated by post-translational mechanisms affecting BCL-2 family members among others. Additionally, we found that IL-4 signaling has a stabilizing effect on the surface expression levels of the critical basophil activation receptor FcεRI. In summary, our findings indicate an important regulatory role of IL-4 on in vitro-differentiated mouse basophils enhancing their survival and stabilizing FcεRI receptor expression through PI3K-dependent signaling. A better understanding of the regulation of basophil survival will help to define promising targets and consequently treatment strategies in basophil-driven diseases.
Highlights
The source of interleukin (IL)-4 in vivo is thought to derive upon activation from at least three different cell types, including mast cells, basophils as well as a subpopulation of T cells
Throughout this study, we traced the impact of Interleukin 4 (IL-4) on survival of basophils using the IL-3condHoxb[8] model of in vitro-differentiated mouse basophils[20,21]
In vitro-differentiated mouse basophils spontaneously underwent apoptotic cell death, as assessed by flow cytometric analysis of cellular viability over time (Fig. 1a). This effect could be significantly delayed by the administration of recombinant IL-4, even though the impact was less potent compared to IL-3, which is a well-known and critical pro-survival cytokine for basophils
Summary
The source of interleukin (IL)-4 in vivo is thought to derive upon activation from at least three different cell types, including mast cells, basophils as well as a subpopulation of T cells. IL-4 acts as a prominent cytokine in type 2 immune reactions fulfilling diverse functions. In T cells, upon activation of naive peripheral CD4+ T cells autocrine IL-4 drives their cellular growth and differentiation[1]. Naive T cells mature into TH2 cells leading to the initiation of TH2 immune reactions. IL-4 represents a Official journal of the Cell Death Differentiation Association. Independent activation, de novo-synthesized cytokines such as IL-4 are released from mast cells and basophils[6]. IL-4 serves as a growth factor for human intestinal mast cells and enhances IgEdependent mediator release[6] and promotes de novo expression of other cytokines, such as IL-3, IL-5 and IL-13, whereas the production of IL-6 is suppressed[7]
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