Human Monocytes - CD14, CD16 - Ziegler-Heitbrock

Contact

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

Abstract

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 (O2*-). 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 O2*-. 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-kappaB 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 O2*- production. These data demonstrate that the increase in and/or maintenance of O2*- 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-kappaB pathway. This novel finding supports a model, whereby TNF-alpha-dependent activation of NF-kappaB up-regulates phagocyte NADPH oxidase activity, leading to enhanced ROS production and further NF-kappaB activation, potentially contributing to sustained oxidant production in chronic inflammation.

Authors: Gauss KA, Nelson-Overton LK, Siemsen DW, Gao Y, DeLeo FR, Quinn MT
Journal: J Leukoc Biol.; 82(3):729-741
Year: 2007
PubMed: Find in PubMed