Role of NF-κB in transcriptional regulation of the phagocyte NADPH oxidase by tumor necrosis factor-α
Role of NF-κB in transcriptional regulation of the phagocyte NADPH oxidase by tumor necrosis factor-α
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DOI：
10.1189/jlb.1206735
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发表时间：
2007-09-01
影响因子：
5.5
通讯作者：
Quinn, Mark T.
中科院分区：
文献类型：
--
作者：
Gauss, Katherine A.;Nelson-Overton, Laura K.;Quinn, Mark T.
巨噬细胞在慢性炎症性疾病的发病机制中起重要作用。这些吞噬细胞的活化诱导促炎细胞因子如IL-1和TNF-α的产生以及活性氧物质（ROS）如超氧阴离子（O-2（中心点-））的产生。最近，我们发现TNF-α处理人单核细胞（MonoMac 1）和分离的人单核细胞导致NADPH氧化酶基因，中性粒细胞胞质因子2（NCF 2）的上调。这些结果表明，由活化的巨噬细胞产生的TNF-α可以作为氧化酶的自分泌/旁分泌调节剂，导致O-2的产生增加和/或延长（中心点-）。为了更好地了解TNF-α调节NADPH氧化酶的机制，我们评估了MonoMac 1细胞和人单核细胞中氧化酶基因的转录调节。我们发现，TNF-α处理的细胞有增加的mRNA水平和上调表达的NADPH氧化酶亚基p47（phox），p67（phox），和gp 91（phox），以及增加氧化酶活性。NF-κ B激活的药理学抑制剂阻断了TNF-α诱导的NCF 1、NCF 2和CYBB信息的上调，这与相应氧化酶蛋白表达的减少和O-2（中心点-）产生的减少相关。这些数据表明，TNF-α处理的MonoMac 1细胞和单核细胞中O-2（中心点-）产生的增加和/或维持部分是通过NF-κ B途径转录上调三种必需NADPH氧化酶基因的结果。这一新的发现支持了一种模型，即TNF-α依赖的NF-κ B激活上调吞噬细胞NADPH氧化酶活性，导致ROS产生增加和进一步的NF-κ B激活，可能有助于慢性炎症中持续的氧化剂产生。
Macrophages play an important role in the pathogenesis of chronic inflammatory disease. Activation of these phagocytes induces the production of proinflammatory cytokines, such as IL-1 and TNF-alpha and the generation of reactive oxygen species (ROS), such as superoxide anion (O-2(center dot-)). Recently, we found that TNF-alpha treatment of human monocytic cells (MonoMac1) and isolated human monocytes resulted in up-regulation of the NADPH oxidase gene, neutrophil cytosolic factor 2 (NCF2). These results suggested that TNF-alpha, produced by activated macrophages, could serve as an autocrine/paracrine regulator of the oxidase, resulting in increased and/or prolonged production of O-2(center dot-). To gain a better understanding of the mechanisms involved in NADPH oxidase regulation by TNF-alpha, we evaluated transcriptional regulation of oxidase genes in MonoMac1 cells and human monocytes. We show that TNF-alpha-treated cells have increased levels of mRNA and up-regulated expression of NADPH oxidase subunits p47(phox), p67(phox), and gp91(phox), as well as increased oxidase activity. Pharmacological inhibitors of NF-kappa B activation blocked TNF-alpha-induced up-regulation of NCF1, NCF2, and CYBB message, which correlated with a reduction in expression of the corresponding oxidase proteins and decreased O-2(center dot-) production. These data demonstrate that the increase in and/or maintenance of O-2(center dot-) production in TNF-alpha-treated MonoMac1 cells and monocytes are a result, in part, of transcriptional up-regulation of three essential NADPH oxidase genes via the NF-kappa B pathway. This novel finding supports a model, whereby TNF-alpha-dependent activation of NF-kappa B up-regulates phagocyte NADPH oxidase activity, leading to enhanced ROS production and further NF-kappa B activation, potentially contributing to sustained oxidant production in chronic inflammation.