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J. Biol. Chem., Vol. 282, Issue 28, 20301-20308, July 13, 2007

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Sustained Hydrogen Peroxide Induces Iron Uptake by Transferrin Receptor-1 Independent of the Iron Regulatory Protein/Iron-responsive Element Network^*

Bill Andriopoulos, Stephan Hegedüsch, Julia Mangin, Hans-Dieter Riedel, Ulrike Hebling, Jian Wang, Kostas Pantopoulos^¶, and Sebastian Mueller^||1

From the Department of Internal Medicine, Salem Medical Center, University of Heidelberg, Zeppelinstrasse 11-33, 69121 Heidelberg, Germany, the Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, 3755 Cote-Ste-Catherine Road, Montreal, Quebec H3T 1E2, Canada, the ^¶Department of Medicine, McGill University, Montreal, Quebec H3T 1E2, Canada, and the ^||Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massaschusetts 02215

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 up-regulation 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 or significant protein stabilization. In contrast, pulse experiments with ³⁵S-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.

Received for publication, March 22, 2007

^* This work was supported by grants from the University of Heidelberg, the Alexander von Humboldt foundation the Canadian Liver Foundation, the Deutsche Forschungsgemein schaft, the Dietmar Hopp Foundation, and the Canadian Institutes of Health Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave., Dana 501, Boston, MA 02215. Tel.: 617-667-0571; Fax: 617-667-2767; E-mail: smueller{at}bidmc.harvard.edu or sebastian.mueller{at}urz.uni-heidelberg.de.

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