Essential role for the p110δ phosphoinositide 3-kinase in the allergic response
Essential role for the p110δ phosphoinositide 3-kinase in the allergic response
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DOI：
10.1038/nature02991
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发表时间：
2004-10-21
期刊：
影响因子：
64.8
通讯作者：
Vanhaesebroeck, B
中科院分区：
文献类型：
--
作者：
Ali, K;Bilancio, A;Vanhaesebroeck, B
肥大细胞释放的炎症物质诱导并维持过敏反应（1,2）。肥大细胞的分化和活化分别受干细胞因子（SCF；也称为Kit配体）以及与过敏原特异性免疫球蛋白E（IgE）结合的过敏原所调节（2,3）。活化的SCF受体和IgE的高亲和力受体（FcεRI）与磷脂酰肌醇3 - 激酶（PI(3)Ks）结合，产生细胞内脂质第二信使信号（2 - 5）。在此，我们报道在肥大细胞中PI(3)K的p110δ异构体通过基因或药物失活，导致SCF介导的体外增殖、黏附和迁移出现缺陷，以及过敏原 - IgE诱导的脱颗粒和细胞因子释放受损。p110δ失活可保护小鼠免受过敏性过敏反应。这些结果确定p110δ是过敏和肥大细胞相关疾病治疗干预的一个新靶点。
Inflammatory substances released by mast cells induce and maintain the allergic response(1,2). Mast cell differentiation and activation are regulated, respectively, by stem cell factor (SCF; also known as Kit ligand) and by allergen in complex with allergen-specific immunoglobulin E (IgE)(2,3). Activated SCF receptors and high-affinity receptors for IgE (FcepsilonRI) engage phosphoinositide 3-kinases (PI(3)Ks) to generate intracellular lipid second messenger signals(2-5). Here, we report that genetic or pharmacological inactivation of the p110delta isoform of PI(3) K in mast cells leads to defective SCF-mediated in vitro proliferation, adhesion and migration, and to impaired allergen-IgE-induced degranulation and cytokine release. Inactivation of p110delta protects mice against anaphylactic allergic responses. These results identify p110delta as a new target for therapeutic intervention in allergy and mast-cell-related pathologies.