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 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 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 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 1alpha or significant protein stabilization. In contrast, pulse experiments with (35)S-labeled 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.
Andriopoulos
Bill
B
Department of Internal Medicine, Salem Medical Center, University of Heidelberg, Zeppelinstrasse 11-33, 69121 Heidelberg, Germany.
Hegedüsch
Stephan
S
Mangin
Julia
J
Riedel
Hans-Dieter
HD
Hebling
Ulrike
U
Wang
Jian
J
Pantopoulos
Kostas
K
Mueller
Sebastian
S
D015703:Antigens, CD / Q000096:biosynthesis*; D005293:Ferritins / Q000378:metabolism; D006367:HeLa Cells; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007501:Iron / Q000378:metabolism* / Q000494:pharmacology; D035925:Iron-Regulatory Proteins / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D011990:Receptors, Transferrin / Q000096:biosynthesis*; D020218:Response Elements; D015533:Transcriptional Activation / Q000187:drug effects; D014168:Transferrin / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D015703:Antigens, CD; C068126:CD71 antigen; C045076:Fenton's reagent; D035925:Iron-Regulatory Proteins; D011990:Receptors, Transferrin; D014168:Transferrin; D005293:Ferritins; D006861:Hydrogen Peroxide; D007501:Iron