Curcurnin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element
Curcurnin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element
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DOI：
10.1042/bj20021619
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发表时间：
2003-05-01
影响因子：
4.1
通讯作者：
Motterlini, R
中科院分区：
文献类型：
--
作者：
Balogun, E;Hoque, M;Motterlini, R
转录因子Nrf 2，通常存在于一个非活性状态的结果，结合到一个细胞因子相关蛋白Keap 1，可以被激活的氧化还原依赖性刺激。Nrf 2-Keap 1相互作用的改变使Nrf 2能够易位到细胞核，与抗氧化剂反应元件（ARE）结合，并启动编码解毒酶和细胞保护蛋白的基因的转录。这种反应也是由一类亲电化合物引发的，包括多酚和植物衍生成分。最近，天然抗氧化剂姜黄素和咖啡酸苯乙酯（CAPE）已被确定为血红素加氧酶-1（HO-1）的有效诱导剂，血红素加氧酶-1（HO-1）是一种氧化还原敏感的诱导蛋白，可提供对各种形式的应激的保护。在这里，我们表明，在肾上皮细胞中，姜黄素和CAPE刺激Nrf 2的表达在浓度和时间依赖性的方式。这种效应与HO-1蛋白表达和血红素加氧酶活性的显著增加有关。从几条线的调查，我们还报告说，姜黄素（和，通过推理，CAPE）刺激ho-1基因活性，促进Nrf 2-Keap 1复合物的失活，导致增加Nrf 2结合居民ho-1战神。此外，使用抗体和丝裂原活化蛋白激酶（MAPK）途径的特异性抑制剂，我们提供的数据暗示p38 MAPK在姜黄素介导的ho-1诱导。综上所述，这些结果表明姜黄素和CAPE诱导HO-1需要激活Nrf 2/ARE途径。
The transcription factor Nrf2, which normally exists in an inactive state as a consequence of binding to a cytoskeleton-associated protein Keap1, can be activated by redox-dependent stimuli. Alteration of the Nrf2-Keap1 interaction enables Nrf2 to translocate to the nucleus, bind to the antioxidant-responsive element (ARE) and initiate the transcription of genes coding for detoxifying enzymes and cytoprotective proteins. This response is also triggered by a class of electrophilic compounds including polyphenols and plant-derived constituents. Recently, the natural antioxidants curcumin and caffeic acid phenethyl ester (CAPE) have been identified as potent inducers of haem oxygenase-1 (HO-1), a redox-sensitive inducible protein that provides protection against various forms of stress. Here, we show that in renal epithelial cells both curcumin and CAPE stimulate the expression of Nrf2 in a concentration- and time-dependent manner. This effect was associated with a significant increase in HO-1 protein expression and haem oxygenase activity. From several lines of investigation we also report that curcumin (and, by inference, CAPE) stimulates ho-1 gene activity by promoting inactivation of the Nrf2-Keap1 complex, leading to increased Nrf2 binding to the resident ho-1 AREs. Moreover, using antibodies and specific inhibitors of the mitogen-activated protein kinase (MAPK) pathways, we provide data implicating p38 MAPK in curcumin-mediated ho-1 induction. Taken together, these results demonstrate that induction of HO-1 by curcumin and CAPE requires the activation of the Nrf2/ARE pathway.