PIP3 regulation as promising targeted therapy of mast-cell-mediated diseases.
PIP3 regulation as promising targeted therapy of mast-cell-mediated diseases.
复制标题
DOI：
10.2174/138161211798357926
复制
发表时间：
2011-10
影响因子：
3.1
通讯作者：
B. Shenker;H. Ali;K. Boesze-Battaglia
中科院分区：
文献类型：
--
作者：
B. Shenker;H. Ali;K. Boesze-Battaglia
已证实肥大细胞在过敏和炎症中起关键调节作用，涉及抗原与结合至高亲和力IgE受体（FcεRI）的IgE的接合。调节肥大细胞功能的最积极的努力集中在选择性抑制细胞活化和随后的介质合成和释放，或者阻断促炎介质的作用，以预防或降低疾病的严重程度。最近，合理设计的药物治疗的目标已将焦点转移到靶向和破坏导致抑制特定细胞功能的信号传导途径。在这种情况下，PI-3 K/PIP 3/Akt通路代表了肥大细胞介导的炎症性疾病中药理学干预的有效靶点。该级联的关键组分是磷脂酰肌醇-3-激酶（PI-3 K）的活化，导致细胞内3，4，5-三磷酸磷脂酰肌醇（PIP 3）水平的升高。PIP 3对肥大细胞信号传导和功能以及增殖和存活具有广泛的影响。我们认为PIP 3是一个有效的靶点，可用于开发下调肥大细胞功能的治疗方法，进而降低肥大细胞依赖性疾病的严重程度。在这篇文章中，我们已采取的方法来调节肥大细胞PI-3 K通路。此外，我们回顾了一种新的方法来靶向信号脂质PIP 3，并使用由IgE的FcεRI结合区和细胞致死膨胀毒素CdtB的活性亚基组成的嵌合毒素来消耗这种磷酸肌醇的细胞内水平，CdtB是我们最近证明作为PIP 3磷酸酶发挥作用的。
It is well established that mast cells play a key regulatory role in allergy and inflammation involving engagement of antigen with IgE bound to high-affinity IgE receptors (FcεRI). The most aggressive efforts in regulating mast cell function have focused on selectively inhibiting cell activation and subsequent mediator synthesis and release, or alternatively, blocking the action of proinflammatory mediators in order to prevent or reduce disease severity. More recently, the goal for rationally designed pharmacotherapy has shifted focus to targeting and disrupting signaling pathways leading to inhibition of specific cell function(s). In this context, the PI-3K/PIP3/Akt pathway represents a potent target for pharmacologic intervention in mast cell-mediated inflammatory disorders. A pivotal component of this cascade is the activation of phosphatidylinositol-3-kinase (PI-3K) leading to a rise in intracellular levels of phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 has broad effects on mast cell signaling and function as well as on proliferation and survival. We propose that PIP3 represents a potent target for developing therapeutic approaches to down regulate mast cell function and, in turn, reduce the severity of mast cell dependent disease. In this article we review approaches that have been taken to regulate the PI-3K pathway in mast cells. Moreover, we review a novel approach to target the signaling lipid, PIP3, and deplete intracellular levels of this phosphoinositol using a chimeric toxin composed of the FcεRI binding region of IgE and the active subunit of the cytolethal distending toxin, CdtB, which we have recently demonstrated to function as a PIP3 phosphatase.