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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 H 2 O 2 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 H 2 O 2 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 H 2 O 2 , 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␣ or significant protein stabilization. In contrast, pulse experiments with 35 Slabeled methionine/cysteine revealed an increased rate of TfR1 synthesis in cells exposed to sustained low H 2 O 2 levels. Our results suggest a novel mechanism of iron accumulation by sustained H 2 O 2 , based on the translational activation of TfR1, which could provide an important (patho)physiological link between iron metabolism and inflammation.Systemic iron homeostasis undergoes typical changes during inflammatory or infectious conditions. A decrease in plasma iron concentration limits the availability of the metal for erythropoiesis, ultimately leading to the so-called anemia of chronic disease (1). In addition to iron retention within the reticuloendothelial system, parenchymal cells such as hepatocytes also accumulate iron under inflammatory conditions (2-8), and this iron deposition has been identified as an important factor in tissue damage by free radicals (9). In addition, hepatic iron accumulation appears to be an important cofactor in the development of fibrosis and end stage liver disease in such common chronic liver pathologies such as hepatitis C or alcoholic steatohepatitis (4 -8).Significant progress has been made toward understanding the molecular basis of iron retention within the reticuloendothelial system during inflammation (10 -12). The mechanism involves the interleukin-6-mediated induction of the iron-regulatory peptide hepcidin (13, 14), which inhibits iron efflux from macrophages and intestinal enterocytes (15, 16) by binding to and promoting the degradation of the transporter ferroportin 1 (IREG1 or MTP1) (17). The ensuing hypoferremia is thought to be part of a physiological defense strategy to deplete invading bacteria from the growth-essential iron. Thus far, the possibility that inflammation-mediated accumulation of iron in parenchymal cells may also contribute to hypoferremia has not received much attention. Nevertheless, the expression of transferrin receptor 1 (TfR1), 2 the major iron uptake protein, is induced in several models of inflammation (2, 18).Upon activation, inflammatory cells su...

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