Tumor necrosis factor alpha increases reactive oxygen species production and induces DNA damage by inducing spermine oxidase in human lung bronchial epithelial cells in vitro: Potential mechanism for inflammation induced lung carcinogenesis.

B66

Recurrent or chronic inflammation has been implicated in thedevelopment of many human epithelial cancers, including those of the stomach, lung, colon and prostate. Tumor necrosis factor α (TNFα) is a potent pleiotropic, proinflammatory cytokine produced by many cells in response to inflammation. Chronically produced TNFα acts as an endogenous tumor promoter by contributing to the tissue remodeling and stromal development necessary for tumor growth and spread. Our previous studies with H. pylori in gastric epithelial cells suggest that spermine oxidase (SMO/PAOh1), a polyamine catabolic enzyme which oxidizes spermine into spermidine, 3-aminopropanal and H₂O₂, is an inflammatory response gene. Here we show that TNFα exposure leads to a significant increase in the production of reactive oxygen species (ROS), with a concomitant increase in the production of 8-oxo-deoxyguanosine, a marker for oxidative DNA damage, in the Beas-2B and HBEC-3K human lung bronchial epithelial cells. Further, inhibition of TNFα-induced SMO/PAOh1 activity with MDL 72,527 or with a targeted siRNA prevented ROS production and oxidative DNA damage, thereby indicating SMO as the source of ROS in TNFα-treated Beas-2B cells. Further, similar induction in SMO/PAOh1 is observed with treatment of another inflammatory cytokine, IL-6. The data are consistent with a model that directly links inflammation and DNA damage through the production of H₂O₂ by SMO/PAOh1. Further, these results suggest a common pathway by which inflammation from multiple sources can lead to the mutagenic changes necessary for the development and progression of epithelial cancers.