hsBAFF promotes proliferation and survival in cultured B lymphocytes via calcium signaling activation of mTOR pathway
hsBAFF promotes proliferation and survival in cultured B lymphocytes via calcium signaling activation of mTOR pathway
复制标题
hsBAFF 通过 mTOR 通路的钙信号激活促进培养 B 淋巴细胞的增殖和存活
DOI：
10.1016/j.cyto.2013.03.011
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发表时间：
2013-05-01
期刊：
影响因子：
3.8
通讯作者：
Chen, Long
中科院分区：
文献类型：
--
作者：
Ke, Zhen;Liang, Dingfang;Chen, Long
TNF家族的B细胞活化因子（BAFF，也称为BLyS、TALL-1、THANK或zTNF 4）已揭示其在B淋巴细胞增殖和存活以及自身免疫性疾病的发病机制中的关键功能。然而，过量的BAFF扩展的攻击性B淋巴细胞的分子机制尚未完全确定。在这里，我们发现过量的hsBAFF升高的[Ca 2 +]（i）激活哺乳动物雷帕霉素靶蛋白（mTOR）信号通路，导致B淋巴细胞的增殖和存活。这得到了细胞内Ca 2+螯合剂（BAPTA/AM）或mTOR抑制剂（雷帕霉素）消除这些事件的发现的支持。随后，我们观察到使用EGTA或2-AP B防止[Ca 2 +]（i）升高显著抑制了mTOR信号传导的hsBAFF活化以及细胞生长和存活，表明hsBAFF诱导的细胞外Ca 2+内流和ER Ca 2+释放升高了[Ca 2 +]（i），从而通过mTOR信号传导的活化促进B淋巴细胞增殖和存活。此外，我们注意到用BAPTA/AM、EGTA或2-APB预处理阻断hsBAFF增加的钙/钙调蛋白依赖性蛋白激酶II（CaMKII）磷酸化，并用KN 93抑制CaMKII减弱hsBAFF激活的mTOR信号传导，以及细胞生长和存活，揭示了hsBAFF升高[Ca 2 +]（i）的作用，对mTOR信号传导以及B淋巴细胞增殖和存活的影响是通过刺激CaMK II的磷酸化。结果表明，hsBAFF激活mTOR通路，通过钙信号传导触发B淋巴细胞增殖和存活。我们的研究结果表明，细胞内Ca 2+水平或CaMK II和mTOR活性的操纵可用于预防过度BAFF诱导的侵袭性B淋巴细胞疾病和自身免疫性疾病。(C)2013爱思唯尔有限公司保留所有权利。
B-cell activating factor of the TNF family (BAFF, also called BLyS, TALL-1, THANK, or zTNF4) has revealed its critical function in B lymphocyte proliferation and survival, as well as the pathogenesis of autoimmune disease. However, the molecular mechanisms of excess BAFF-extended aggressive B lymphocytes have not been completely defined. Here we show that excessive hsBAFF-elevated [Ca2+](i) activated mammalian target of rapamycin (mTOR) signaling pathway, leading to proliferation and survival in B lymphocytes. This is supported by the findings that intracellular Ca2+ chelator (BAPTA/AM) or mTOR inhibitor (rapamycin) abolished the events. Sequentially, we observed that preventing [Ca2+](i) elevation using EGTA or 2-APB dramatically inhibited hsBAFF activation of mTOR signaling, as well as cell growth and survival, suggesting that hsBAFF-induced extracellular Ca2+ influx and ER Ca2+ release elevates [Ca2+](i) contributing to B lymphocyte proliferation and survival via activation of mTOR signaling. Further, we noticed that pretreatment with BAPTA/AM, EGTA or 2-APB blocked hsBAFF-increased phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII), and inhibiting CaMKII with KN93 attenuated hsBAFF-activated mTOR signaling, as well as cell growth and survival, revealing that the effects of hsBAFF-elevated [Ca2+](i) on mTOR signaling as well as proliferation and survival in B lymphocytes is through stimulating phosphorylation of CaMKII. The results indicate that hsBAFF activates mTOR pathway triggering B lymphocyte proliferation and survival by calcium signaling. Our findings suggest that manipulation of intracellular Ca2+ level or CaMKII and mTOR activity may be exploited for the prevention of excessive BAFF-induced aggressive B lymphocyte disorders and autoimmune diseases. (C) 2013 Elsevier Ltd. All rights reserved.