SLP-76 is required for high-affinity IgE receptor- and IL-3 receptor-mediated activation of basophils.
SLP-76 is required for high-affinity IgE receptor- and IL-3 receptor-mediated activation of basophils.
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SLP-76 是高亲和力 IgE 受体和 IL-3 受体介导的嗜碱性粒细胞激活所必需的。
DOI：
10.1093/intimm/dxs072
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发表时间：
2012
影响因子：
4.4
通讯作者：
Shinya Hidano
中科院分区：
文献类型：
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作者：
Caganova M;Carrisi C;Varano G;Mainoldi F;Zanardi F;Germain PL;George L;Alberghini F;Ferrarini L;Talukder AK;Ponzoni M;Testa G;Nojima T;Doglioni C;Kitamura D,;Yohei Kawano;Shinya Hidano
据报道，嗜碱性粒细胞在过敏性炎症中发挥关键作用，它通过分泌IL-4来响应IL-3或高亲和力ε受体(Fc-Ig RI)-交联性。然而，FcεRI下游的信号通路和嗜碱性粒细胞中的IL-3受体尚不清楚。在本研究中，我们使用SLP-76(76 kDa的src同源2区含白细胞磷蛋白)缺陷的小鼠来展示该接头分子在转导FcεRI和IL-3受体介导的诱导嗜碱性细胞激活的信号中的关键功能。尽管SLP-76在体内分化和IL-3诱导的嗜碱性粒细胞体外增殖中是必不可少的，但这两种刺激诱导的IL-4的产生都完全被SLP-76缺乏所消融。生化分析表明，在缺乏γ-76的嗜碱性粒细胞中，IL-3诱导的磷脂酶C(PLC)ε-2和AKT的磷酸化水平显著降低，而STAT5的磷酸化水平没有明显降低，而Fc-γRI的交联型磷酸化水平被SLP-76缺乏所抑制，这表明在嗜碱性粒细胞中FcεRI和IL-3受体介导的信号通路对AKT激活的需求存在重要差异。由于IL-3诱导的IL-4产生对钙调神经磷酸酶抑制剂和细胞内钙离子螯合剂敏感，除PI3K抑制剂外，SLP-76可能通过介导嗜碱性粒细胞中εγ2的激活来调节Fc PLC RI-和IL-3受体诱导的IL-4产生。综上所述，这些发现表明，SLP-76是FcεRI和IL-3受体下游嗜碱性粒细胞激活的重要信号成分。
Basophils have been reported to play a critical role in allergic inflammation by secreting IL-4 in response to IL-3 or high-affinity IgE receptor (FcεRI)-cross-linking. However, the signaling pathways downstream of FcεRI and the IL-3 receptor in basophils have yet to be determined. In the present study, we used mice deficient in SLP-76 (Src homology 2 domain-containing leukocyte phosphoprotein of 76kDa) to demonstrate critical functions of this adaptor molecule in transducing FcεRI- and IL-3 receptor-mediated signals that induce basophil activation. Although SLP-76 was dispensable forin vivodifferentiation, as well as IL-3-inducedin vitroproliferation of basophils, IL-4 production induced by both stimuli was completely ablated by SLP-76 deficiency. Biochemical analyses revealed that IL-3-induced phosphorylation of phospholipase C (PLC) γ2 and Akt, but not STAT5, was severely reduced in SLP-76-deficient basophils, whereas FcεRI cross-linking phosphorylation of PLCγ2, but not Akt, was abrogated by SLP-76 deficiency, suggesting important differences in the requirement of SLP-76 for Akt activation between FcεRI- and IL-3 receptor-mediated signaling pathways in basophils. Because IL-3-induced IL-4 production was sensitive to calcineurin inhibitors and an intracellular calcium chelator, in addition to PI3K inhibitors, SLP-76 appears to regulate FcεRI- and IL-3 receptor-induced IL-4 production via mediating PLCγ2 activation in basophils. Taken together, these findings indicate that SLP-76 is an essential signaling component for basophil activation downstream of both FcεRI and the IL-3 receptor.