The pleiotropic cytokine tumor necrosis factor alpha (TNF-alpha) can induce apoptosis but also supports cell survival pathways. Among the possible anti-apoptotic mechanisms of TNF-alpha is the activation of the transcription factor NF-kappaB. Since reactive oxygen species (ROS) are assumed to contribute to TNF-alpha mediated cytotoxicity but can also facilitate NF-kappaB activation this study investigates the relationship between TNF-alpha treatment, NF-kappaB activation and the expression of the anti-oxidative enzyme catalase. TNF-alpha treatment caused downregulation of catalase expression in MCF-7, Caco-2 and Hct-116 cancer cell lines. Overexpression of catalase in MCF-7 cells, resulting in lower intracellular ROS levels upon challenge with H(2)O(2), caused a transient nuclear p65 translocation upon TNF-alpha treatment as compared to the sustained NF-kappaB activation in wild type cells. This was due to a lack of sufficient H(2)O(2) to co-stimulate NF-kappaB activation as demonstrated by the observation that addition of exogenous H(2)O(2) led to a second increase of NF-kappaB activity. The rapid decline of nuclear translocation of NF-kappaB in the catalase overexpressing cells resulted in a slower increase of NF-kappaB mediated reporter gene expression. These results indicate that TNF-alpha mediated downregulation of catalase expression and accordingly sufficient H(2)O(2) is required for appropriate function of the NF-kappaB dependent survival pathway.
2007 Wiley-Liss, Inc.