School of Pharmacy, University of East Anglia, Norwich NR4 7TJ, United Kingdom.
J Immunol. 2011 Jul 15;187(2):702-7. doi: 10.4049/jimmunol.1004117. Epub 2011 Jun 13.
Modulation of monocyte function is a critical factor in the resolution of inflammatory responses. This role is mediated mainly by the production of TNF-α. Investigations of the actions of TNF have mostly focused on acute activation of other cell types such as fibroblasts and endothelial cells. Less is known about the effects of TNF on monocytes themselves, and little is known about the regulation of cell responses to TNF beyond the activation of NF-κB. In this study, we investigated the regulation of NF-E2-related factor 2 (Nrf2) cyctoprotective responses to TNF in human monocytes. We found that in monocytes TNF induces sustained Nrf2 activation and Nrf2 cytoprotective gene induction in a TNFR1-dependent manner. Under TNF activation, monocytes increased their expression of Nrf2-dependent genes, including NAD(P)H:quinone oxidoreductase 1 and glutamyl cysteine ligase modulatory, but not heme oxygenase-1. We also showed that autocrine TNF secretion was responsible for this sustained Nrf2 response and that Nrf2 activation by TNF was mediated by the generation of reactive oxygen species. Moreover, we showed that Nrf2-mediated gene induction can modulate TNF-induced NF-κB activation. These results show for the first time, to our knowledge, that TNF modulates prolonged Nrf2-induced gene expression, which in turn regulates TNF-induced inflammatory responses.
单核细胞功能的调节是炎症反应消退的关键因素。这种作用主要是通过 TNF-α 的产生来介导的。对 TNF 作用的研究大多集中在对成纤维细胞和内皮细胞等其他细胞类型的急性激活上。关于 TNF 对单核细胞本身的影响知之甚少，而且除了 NF-κB 的激活之外，对细胞对 TNF 反应的调节知之甚少。在这项研究中，我们研究了 NF-E2 相关因子 2 (Nrf2) 对 TNF 诱导的人单核细胞细胞保护反应的调节作用。我们发现，在单核细胞中，TNF 以 TNFR1 依赖性的方式诱导持续的 Nrf2 激活和 Nrf2 细胞保护基因诱导。在 TNF 激活下，单核细胞增加了 Nrf2 依赖性基因的表达，包括 NAD(P)H：醌氧化还原酶 1 和谷氨酰半胱氨酸连接酶调节亚基，但不包括血红素加氧酶-1。我们还表明，自分泌 TNF 分泌是这种持续的 Nrf2 反应的原因，并且 TNF 通过生成活性氧来介导 Nrf2 的激活。此外，我们表明 Nrf2 介导的基因诱导可以调节 TNF 诱导的 NF-κB 激活。这些结果首次表明，TNF 调节延长的 Nrf2 诱导基因表达，而这反过来又调节 TNF 诱导的炎症反应。
