Institute of Pharmacology, University of Bern, Bern, Switzerland.
Cell Death Dis. 2018 Jun 18;9(7):713. doi: 10.1038/s41419-018-0754-z.
Interleukin 4 (IL-4) is a critical cytokine implicated with T2 immune reactions, which are linked to pathologic conditions of allergic diseases. In that context, the initiation of T2 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.
白细胞介素 4（IL-4）是一种与 T2 免疫反应有关的关键细胞因子，T2 免疫反应与过敏疾病的病理状况有关。在这种情况下，T2 反应的启动可能严重依赖于早期嗜碱性粒细胞衍生的 IL-4 来激活 T 细胞反应，然后放大 IL-4 的分泌。作为一种多效细胞因子，IL-4 作用于广泛的造血和非造血细胞。然而，IL-4 对嗜碱性粒细胞本身的作用，嗜碱性粒细胞作为过敏和自身免疫疾病的相关参与者，迄今为止还很少被涉及。在这里，我们使用体外分化的小鼠嗜碱性粒细胞来研究 IL-4 对细胞活力和 IgE 高亲和力受体 FcεRI 表面表达的直接影响。我们观察到 IL-4 在嗜碱性粒细胞中引发明显的存活信号，在体外延迟自发凋亡的程度可与已知的 IL-3 的存活效应相媲美。我们的数据表明，IL-4 介导的存活依赖于 PI3K/AKT 信号，与 IL-3 不同，它在很大程度上独立于转录变化，而是通过影响 BCL-2 家族成员等的翻译后机制来实现。此外，我们发现 IL-4 信号对关键的嗜碱性粒细胞激活受体 FcεRI 的表面表达水平具有稳定作用。总之，我们的研究结果表明，IL-4 在体外分化的小鼠嗜碱性粒细胞中具有重要的调节作用，通过 PI3K 依赖性信号增强其存活并稳定 FcεRI 受体表达。更好地了解嗜碱性粒细胞存活的调节将有助于确定在嗜碱性粒细胞驱动的疾病中有希望的治疗靶点和策略。
