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Role of NF‐κB in transcriptional regulation of the phagocyte NADPH oxidase by tumor necrosis factor‐α
Author(s) -
Gauss Katherine A.,
NelsonOverton Laura K.,
Siemsen Daniel W.,
Gao Ying,
DeLeo Frank R.,
Quinn Mark T.
Publication year - 2007
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.1206735
Subject(s) - phagocyte , nadph oxidase , biology , tumor necrosis factor alpha , microbiology and biotechnology , nf κb , tumor necrosis factor α , nfkb1 , mononuclear phagocyte system , reactive oxygen species , cancer research , immunology , phagocytosis , transcription factor , biochemistry , gene , signal transduction
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‐α and the generation of reactive oxygen species (ROS), such as superoxide anion (O 2 •– ). Recently, we found that TNF‐α 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‐α, produced by activated macrophages, could serve as an autocrine/paracrine regulator of the oxidase, resulting in increased and/or prolonged production of O 2 •– . To gain a better understanding of the mechanisms involved in NADPH oxidase regulation by TNF‐α, we evaluated transcriptional regulation of oxidase genes in MonoMac1 cells and human monocytes. We show that TNF‐α‐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‐κB activation blocked TNF‐α‐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 •– production. These data demonstrate that the increase in and/or maintenance of O 2 •– production in TNF‐α‐treated MonoMac1 cells and monocytes are a result, in part, of transcriptional up‐regulation of three essential NADPH oxidase genes via the NF‐κB pathway. This novel finding supports a model, whereby TNF‐α‐dependent activation of NF‐κB up‐regulates phagocyte NADPH oxidase activity, leading to enhanced ROS production and further NF‐κB activation, potentially contributing to sustained oxidant production in chronic inflammation.