Sustained hydrogen peroxide induces iron uptake by transferrin receptor-1 independent of the iron regulatory protein/iron-responsive element network

Local and systemic inflammatory conditions are characterized by the intracellular deposition of excess iron, which may promote tissue damage via Fenton chemistry. Because the Fenton reactant H2O2 is continuously released by inflammatory cells, a tight regulation of iron homeostasis is required. Here, we show that exposure of cultured cells to sustained low levels of H2O2 that mimic its release by inflammatory cells leads to upregulation of transferrin receptor 1 (TfR1), the major iron uptake protein. The increase in TfR1 results in increased transferrin-mediated iron uptake and cellular accumulation of the metal. Although iron regulatory protein 1 is transiently activated by H2O2, this response is not sufficient to stabilize TfR1 mRNA and to repress the synthesis of the iron storage protein ferritin. The induction of TfR1 is also independent of transcriptional activation via hypoxia-inducible factor 1 alpha or significant protein stabilization. In contrast, pulse experiments with S-35-labeled methionine/cysteine revealed an increased rate of TfR1 synthesis in cells exposed to sustained low H2O2 levels. Our results suggest a novel mechanism of iron accumulation by sustained H2O2, based on the translational activation of TfR1, which could provide an important (patho) physiological link between iron metabolism and inflammation.