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Published online before print May 31, 2007

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(Journal of Leukocyte Biology. 2007;82:729-741.)
© 2007 by Society for Leukocyte Biology

Role of NF-B in transcriptional regulation of the phagocyte NADPH oxidase by tumor necrosis factor-

Katherine A. Gauss^*,1, Laura K. Nelson-Overton^*, Daniel W. Siemsen^*, Ying Gao^*, Frank R. DeLeo and Mark T. Quinn^*

^* Department of Veterinary Molecular Biology, Montana State University, Bozeman, Montana, USA; and
Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA

¹ Correspondence: Veterinary Molecular Biology, Montana State University, Bozeman, MT 59717, USA. E-mail: kgauss{at}montana.edu

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- and the generation of reactive oxygen species (ROS), such as superoxide anion (O₂^•–). Recently, we found that TNF- 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-, produced by activated macrophages, could serve as an autocrine/paracrine regulator of the oxidase, resulting in increased and/or prolonged production of O₂^•–. To gain a better understanding of the mechanisms involved in NADPH oxidase regulation by TNF-, we evaluated transcriptional regulation of oxidase genes in MonoMac1 cells and human monocytes. We show that TNF--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-B activation blocked TNF--induced up-regulation of NCF1, NCF2, and CYBB message, which correlated with a reduction in expression of the corresponding oxidase proteins and decreased O₂^•– production. These data demonstrate that the increase in and/or maintenance of O₂^•– production in TNF--treated MonoMac1 cells and monocytes are a result, in part, of transcriptional up-regulation of three essential NADPH oxidase genes via the NF-B pathway. This novel finding supports a model, whereby TNF--dependent activation of NF-B up-regulates phagocyte NADPH oxidase activity, leading to enhanced ROS production and further NF-B activation, potentially contributing to sustained oxidant production in chronic inflammation.

Key Words: promoter • inflammation

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