Mitochondrial STAT3 plays a major role in IgE-antigen-mediated mast cell exocytosis
Mitochondrial STAT3 plays a major role in IgE-antigen-mediated mast cell exocytosis
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DOI：
10.1016/j.jaci.2013.12.1075
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发表时间：
2014-08-01
影响因子：
14.2
通讯作者：
Razin, Ehud
中科院分区：
文献类型：
--
作者：
Erlich, Tal Hadad;Yagil, Zohar;Razin, Ehud
背景资料：线粒体氧化磷酸化（OXPHOS）参与肥大细胞胞吐作用，最近的研究表明，肥大细胞激活后线粒体易位到胞吐位点。与此同时，线粒体信号转导和转录激活因子3（STAT3）被发现参与ATP的产生。然而，调节线粒体STAT3功能及其连接到肥大细胞exocytosis是unknown. Objective：我们试图探讨线粒体STAT3在肥大细胞exocytosis. Methods：实验进行了在体外与人类和小鼠肥大细胞和大鼠嗜碱性白血病（RBL）细胞和在小鼠体内的作用。免疫活化后测定OXPHOS活性。STAT3的表达，细胞外信号调节激酶1/2，和蛋白质抑制剂的活化STAT3在线粒体中的肥大细胞活化过程中被确定，作为STAT3抑制OXPHOS活性和肥大细胞function.Results的影响：在这里，我们表明，线粒体STAT3是必不可少的免疫介导的脱粒的人和小鼠肥大细胞和RBL细胞。此外，在IgE抗原激活的RBL细胞中，线粒体STAT3以细胞外信号调节激酶1/2依赖的方式在丝氨酸727上磷酸化，随后诱导OXPHOS活性。此外，发现STAT3的内源性抑制剂（活化的STAT3的蛋白质抑制剂）抑制线粒体中的OXPHOS活性，导致肥大细胞脱粒的抑制。此外，小鼠注射Stattic，STAT3抑制剂，有一个显着减少组胺secretory.Conclusion：这些结果提供了第一个证据的调节作用，线粒体STAT3在肥大细胞的功能，因此线粒体STAT3可以作为一个新的目标过敏性疾病的操纵。
Background: The involvement of mitochondrial oxidative phosphorylation (OXPHOS) in mast cell exocytosis was recently suggested by the finding that mitochondria translocate to exocytosis sites upon mast cell activation. In parallel, mitochondrial signal transducer and activator of transcription 3 (STAT3) was found to be involved in ATP production. However, the regulation of mitochondrial STAT3 function and its connection to mast cell exocytosis is unknown.Objective: We sought to explore the role played by mitochondrial STAT3 in mast cell exocytosis.Methods: Experiments were performed in vitro with human and mouse mast cells and rat basophilic leukemia (RBL) cells and in vivo in mice. OXPHOS activity was measured after immunologic activation. The expression of STAT3, extracellular signal-regulated kinase 1/2, and protein inhibitor of activated STAT3 in the mitochondria during mast cell activation was determined, as was the effect of STAT3 inhibition on OXPHOS activity and mast cell function.Results: Here we show that mitochondrial STAT3 is essential for immunologically mediated degranulation of human and mouse mast cells and RBL cells. Additionally, in IgE-antigen-activated RBL cells, mitochondrial STAT3 was phosphorylated on serine 727 in an extracellular signal-regulated kinase 1/2-dependent manner, which was followed by induction of OXPHOS activity. Furthermore, the endogenous inhibitor of STAT3, protein inhibitor of activated STAT3, was found to inhibit OXPHOS activity in the mitochondria, resulting in inhibition of mast cell degranulation. Moreover, mice injected with Stattic, a STAT3 inhibitor, had a significant decrease in histamine secretion.Conclusion: These results provide the first evidence of a regulatory role for mitochondrial STAT3 in mast cell functions, and therefore mitochondrial STAT3 could serve as a new target for the manipulation of allergic diseases.