Hypoxia-inducible factor-1α (HIF1α) switches on transient receptor potential ankyrin repeat 1 (TRPA1) gene expression via a hypoxia response element-like motif to modulate cytokine release.
Hypoxia-inducible factor-1α (HIF1α) switches on transient receptor potential ankyrin repeat 1 (TRPA1) gene expression via a hypoxia response element-like motif to modulate cytokine release.
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DOI：
10.1074/jbc.m112.361139
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发表时间：
2012-09-14
期刊：
影响因子：
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通讯作者：
Muraki K
中科院分区：
文献类型：
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作者：
Hatano N;Itoh Y;Suzuki H;Muraki Y;Hayashi H;Onozaki K;Wood IC;Beech DJ;Muraki K
背景：TRPA 1形成Ca 2 +-和Zn 2 +-可渗透的离子通道，可感知有害物质。结果：TNF-α和IL 1-α通过核因子-κB信号和下游HIF 1 α的激活诱导TRPA 1基因表达。结论：HIF 1 α介导炎症介质与离子通道的表达。意义：HIF 1 α通过与TRPA 1基因中的特异性缺氧反应元件样基序及其侧翼区域结合而发挥作用。瞬时受体电位锚蛋白重复序列1（TRPA 1）形成钙（Ca 2+）和锌（Zn 2+）可渗透的离子通道，感知有害物质。尽管TRPA 1的生物学和临床的重要性，有很少的知识，导致TRPA 1的转录调控和转录诱导的TRPA 1的功能作用的机制。在这里，我们显示诱导TRPA 1的炎症介质和描绘的潜在的分子机制和功能的相关性。在人成纤维细胞样滑液细胞中，关键炎症介质（肿瘤坏死因子-α和白细胞介素-1 α）通过核因子-κB信号传导和转录因子缺氧诱导因子-1 α（HIF 1 α）的下游激活来诱导TRPA 1基因表达。HIF 1 α通过与TRPA 1基因中的特异性低氧反应元件样基序及其侧翼区域结合而发挥作用。诱导TRPA 1通道，这是内在激活内源性过氧化氢和锌+，抑制分泌白细胞介素-6和白细胞介素-8。这些数据提示了一种以前未被认识的HIF 1 α机制，它将炎症介质与离子通道表达联系起来。
Background: TRPA1 forms Ca2+- and Zn2+-permeable ion channels that sense noxious substances. Results: TNF-α and IL1-α induce TRPA1 gene expression via nuclear factor-κB signaling and downstream activation of HIF1α. Conclusion: HIF1α links inflammatory mediators to ion channel expression. Significance: HIF1α acts by binding to a specific hypoxia response element-like motif and its flanking regions in the TRPA1 gene. Transient receptor potential ankyrin repeat 1 (TRPA1) forms calcium (Ca2+)- and zinc (Zn2+)-permeable ion channels that sense noxious substances. Despite the biological and clinical importance of TRPA1, there is little knowledge of the mechanisms that lead to transcriptional regulation of TRPA1 and of the functional role of transcriptionally induced TRPA1. Here we show induction of TRPA1 by inflammatory mediators and delineate the underlying molecular mechanisms and functional relevance. In human fibroblast-like synoviocytes, key inflammatory mediators (tumor necrosis factor-α and interleukin-1α) induced TRPA1 gene expression via nuclear factor-κB signaling and downstream activation of the transcription factor hypoxia-inducible factor-1α (HIF1α). HIF1α unexpectedly acted by binding to a specific hypoxia response element-like motif and its flanking regions in the TRPA1 gene. The induced TRPA1 channels, which were intrinsically activated by endogenous hydrogen peroxide and Zn2+, suppressed secretion of interleukin-6 and interleukin-8. The data suggest a previously unrecognized HIF1α mechanism that links inflammatory mediators to ion channel expression.