Histamine regulates cyclooxygenase 2 gene activation through Orai1-mediated NFκB activation in lung cancer cells
Histamine regulates cyclooxygenase 2 gene activation through Orai1-mediated NFκB activation in lung cancer cells
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DOI：
10.1016/j.ceca.2011.04.004
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发表时间：
2011-07-01
期刊：
影响因子：
4
通讯作者：
Chang, Wei-Chiao
中科院分区：
文献类型：
--
作者：
Huang, Wan-Chen;Chai, Chee-Yin;Chang, Wei-Chiao
组胺是一种重要的化学介质，已被证明可以调节炎症和过敏反应。组胺受体的刺激导致细胞质 Ca2+ 显着增加，这可能是由肌醇三磷酸 (IP3) 依赖性钙池操纵的 Ca2+ 通道 (SOC) 介导的。然而，组胺介导的信号传导与环氧合酶 2 (COX-2) 等炎症基因激活之间的联系仍不清楚。我们的研究表明COX-2蛋白在人肺癌细胞中高表达。用 10 μM 组胺刺激后，钙池操纵的 Ca2+ 内流 (SOCE) 和 COX-2 基因表达均被诱发。组胺介导的 COX-2 激活可以通过 2-APB 和 SOC 通道抑制剂 SKF-96365 来预防。此外，COX-2启动子的缺失分析表明，-80 bp和-250 bp之间的区域包含NF kappa B结合位点，是组胺介导信号传导的关键元件。 ORAI1（钙池操纵的钙通道的重要分子之一）的敲除可减弱组胺介导的 COX-2 表达和 NF kappa B 激活。这些结果表明ORAI1介导的NF kappa B激活是一条重要的信号通路，负责传递引发炎症反应的组胺信号。(C) 2011 Elsevier Ltd.保留所有权利。
Histamine, an important chemical mediator, has been shown to regulate inflammation and allergic responses. Stimulation of histamine receptors results in a significant increase in cytoplasmic Ca2+, which could be mediated by inositol trisphosphate (IP3)-dependent store-operated Ca2+ channels (SOC). However, the link between histamine-mediated signaling and activation of inflammatory genes such as cyclooxygenase 2 (COX-2) is still unknown. Our study indicated that the COX-2 protein was highly expressed in human lung cancer cells. Following stimulation with 10 mu M of histamine, both store-operated Ca2+ entry (SOCE) and COX-2 gene expression were evoked. Histamine-mediated COX-2 activation can be prevented by 2-APB and SKF-96365, SOC channel inhibitors. In addition, deletion analysis of the COX-2 promoter suggested that the region between -80 bp and -250 bp, which contains NF kappa B binding sites, is the key element for histamine-mediated signaling. Knocking down ORAI1, one of the essential molecules of store-operated calcium channels, attenuated histamine-mediated COX-2 expression and NF kappa B activation. These results indicated that ORAI1-mediated NF kappa B activation was an important signaling pathway, responsible for transmitting histamine signals that trigger inflammatory reactions.(C) 2011 Elsevier Ltd. All rights reserved.