703 Sustained non-toxic oxidative stress (h2o2) increases hepatic transferrin receptor 1 mediated iron uptake in vitro and in vivo independent of the IL-6/Hepcidin and IRE/IRP1 network

Iron regulatory protein 1 as a sensor of reactive oxygen species

“…Like iron deficiency, H 2 O 2 activates IRP1 for binding to IRE's [66]. Moreover, several other reactive oxygen and nitrogen species have been identified that modulate IRP1 activity [14,49,62,[69][70][71]78]. The IRP1 response towards these reactants is rather complex: While NO [14,71] and H 2 O 2 [49,60,69] induce the activity of IRP1, O ·− 2 [7,12,19,34,41] and HOCl [62] have been shown to block its mRNA binding activity.…”

“…Important for the physiological relevance is that IRP1 is both activated in cultured cells [70] and intact organs [60] when exposed to H 2 O 2 amounts that are readily released by inflammatory cells [57,60]. The oxidative stress-mediated activation of IRP1 is associated with an increase of TfR1 expression in vitro [16,78], increased uptake and intracellular accumulation of transferrin-bound iron [78]. Likewise, the injection of glucose oxidase to rats recapitulates H 2 O 2 release and activates TfR1 expression in the liver [78].…”

“…The oxidative stress-mediated activation of IRP1 is associated with an increase of TfR1 expression in vitro [16,78], increased uptake and intracellular accumulation of transferrin-bound iron [78]. Likewise, the injection of glucose oxidase to rats recapitulates H 2 O 2 release and activates TfR1 expression in the liver [78].…”

“…While the presence of two opposing signals may, at first glance, appear counterintuitive, "balance" principles as determining factors to drive the direction of biochemical pathways also operate in complex cytokine signaling networks. [84] inhibition by menadione, in SOD−/− mice and yeast [5,15,26,55,82,91], induction by doxorubicin [8,45] and in SOD−/− Drosophila [55] inhibition [7,9,12,19,34,41,82] H2O2 rapid activation [9,49,60,68,70] no change [9,70,82] inhibition by transforming into [4Fe-3S] form [9] oxygen decreased by hypoxia and increased by reoxygenation [31,32,52,78],oxygen sensitizes IRP1 as sensor of low iron levels [52] no change [4,52] HOCl blocks H2O2-mediated IRP1 activation [62] irreversible inhibition at unphysiological high levels [62] ? Fig.…”

“…The finding that H 2 O 2 can induce expression of TfR via IRP1 suggests an alternative pathway for ACD [78]. In vitro, the activation of TfR1 by H 2 O 2 results in increased iron uptake and an expansion of the intracellular labile iron pool (LIP).…”