Transcription factor Nrf2 regulates inflammation by mediating the effect of 15-deoxy-Δ12,14-prostaglandin J2
Transcription factor Nrf2 regulates inflammation by mediating the effect of 15-deoxy-Δ12,14-prostaglandin J2
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DOI：
10.1128/mcb.24.1.36-45.2004
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发表时间：
2004-01-01
影响因子：
5.3
通讯作者：
Yamamoto, M
中科院分区：
文献类型：
--
作者：
Itoh, K;Mochizuki, M;Yamamoto, M
激活的巨噬细胞表达高水平的Nrf2，这是一种转录因子，积极调节抗氧化酶和解毒酶的基因表达。在这项研究中，我们研究了Nrf2如何在抗炎过程中发挥作用。作为急性炎症的模型系统，我们用角叉菜胶诱导胸膜炎，发现在NRF2缺陷的小鼠中，中性粒细胞在炎症过程中持续进行组织侵袭，巨噬细胞的募集延迟。用15-脱氧-Delta(12，14)-前列腺素J(2)抗体(15d-PGJ(2))，观察到胸腔灌洗液中巨噬细胞积聚15d-PGJ(2)。在小鼠腹膜巨噬细胞中，15d-PGJ(2)可以通过与Keap1形成加合物来激活Nrf2，导致Nrf2依赖地诱导血红素加氧酶1和过氧化还蛋白I(PrxI)基因表达。给角叉菜胶致胸膜炎的小鼠注射环氧合酶2抑制剂NS-398可使中性粒细胞持续募集，并在巨噬细胞中减弱15d-PGJ(2)的积聚和PrxI的表达。经NS-398处理的野生型小鼠胸膜腔内注射15d-PGJ(2)，可在很大程度上抵消PrxI的降低和中性粒细胞募集的持续。相反，这些变化在Nrf2缺陷小鼠中没有发生。这些结果表明，Nrf2通过协调炎症细胞的招募和调节这些细胞内的基因表达来调节15d-PGJ(2)下游的炎症过程。
Activated macrophages express high levels of Nrf2, a transcription factor that positively regulates the gene expression of antioxidant and detoxication enzymes. In this study, we examined how Nrf2 contributes to the anti-inflammatory process. As a model system of acute inflammation, we administered carrageenan to induce pleurisy and found that in Nrf2-deficient mice, tissue invasion by neutrophils persisted during inflammation and the recruitment of macrophages was delayed. Using an antibody against 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), it was observed that macrophages from pleural lavage accumulate 15d-PGJ(2). We show that in mouse peritoneal macrophages 15d-PGJ(2) can activate Nrf2 by forming adducts with Keap1, resulting in an Nrf2-dependent induction of heme oxygenase 1 and peroxiredoxin I (PrxI) gene expression. Administration of the cyclooxygenase 2 inhibitor NS-398 to mice with carrageenan-induced pleurisy caused persistence of neutrophil recruitment and, in macrophages, attenuated the 15d-PGJ(2) accumulation and PrxI expression. Administration of 15d-PGJ(2) into the pleural space of NS-398-treated wild-type mice largely counteracted both the decrease in PrxI and persistence of neutrophil recruitment. In contrast, these changes did not occur in the Nrf2-deficient mice. These results demonstrate that Nrf2 regulates the inflammation process downstream of 15d-PGJ(2) by orchestrating the recruitment of inflammatory cells and regulating the gene expression within those cells.