Nrf2 is a key transcription factor that regulates antioxidant defense in macrophages and epithelial cells: Protecting against the proinflammatory and oxidizing effects of diesel exhaust chemicals
Nrf2 is a key transcription factor that regulates antioxidant defense in macrophages and epithelial cells: Protecting against the proinflammatory and oxidizing effects of diesel exhaust chemicals
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DOI：
10.4049/jimmunol.173.5.3467
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发表时间：
2004-09-01
影响因子：
4.4
通讯作者：
Nel, AE
中科院分区：
文献类型：
--
作者：
Li, N;Alam, J;Nel, AE
颗粒污染物（包括柴油机排气颗粒（DEP））的促炎作用与其氧化还原循环化学物质的含量及其在呼吸道中产生氧化应激的能力有关。抗氧化防御途径14涉及II相酶表达，可防止DEP的促氧化和促炎作用。酶的表达，包括血红素加氧酶-1（HO-1）和GST，依赖于其启动子中遗传抗氧化反应元件的活性。在这项研究中，我们研究了氧化还原循环的有机化学品，从DEP制备，诱导II相酶的表达作为一种保护性反应的机制。我们证明，分别富含多环芳烃和醌类的芳香族和极性DEP组分会诱导巨噬细胞和上皮细胞中HO-1、GST和其他II相酶的表达。我们发现HO-1的表达是通过bZIP转录因子Nrf 2在细胞核中的积累介导的，而Nrf 2基因靶向显著削弱了这种反应。Nrf 2的积累和随后的抗氧化反应元件的激活受Nrf 2的蛋白酶体降解的调节。该途径对促氧化和亲电DEP化学物质敏感，并且还被周围的超微粒激活。我们认为Nrf 2介导的II相酶表达在过敏性炎症和哮喘的背景下保护颗粒污染物的促炎作用。
The proinflammatory effects of particulate pollutants, including diesel exhaust particles (DEP), are related to their content of redox cycling chemicals and their ability to generate oxidative stress in the respiratory tract. An antioxidant defense pathway, 14 which involves phase II enzyme expression, protects against the pro-oxidative and proinflammatory effects of DEP. The expression of enzymes, including heme oxygenase-1 (HO-1) and GST, is dependent on the activity of a genetic antioxidant response element in their promoters. In this study we investigated the mechanism by which redox cycling organic chemicals, prepared from DEP, induce phase II enzyme expression as a protective response. We demonstrate that aromatic and polar DEP fractions, which are enriched in polycyclic aromatic hydrocarbons and quinones, respectively, induce the expression of HO-1, GST, and other phase II enzymes in macrophages and epithelial cells. We show that HO-1 expression is mediated through accumulation of the bZIP transcription factor, Nrf2, in the nucleus, and that Nrf2 gene targeting significantly weakens this response. Nrf2 accumulation and subsequent activation of the antioxidant response element is regulated by the proteasomal degradation of Nrf2. This pathway is sensitive to pro-oxidative and electrophilic DEP chemicals and is also activated by ambient ultratine particles. We propose that Nrf2-mediated phase II enzyme expression protects against the proinflammatory effects of particulate pollutants in the setting of allergic inflammation and asthma.