Mammalian Tissue Oxygen Levels Modulate Iron-Regulatory Protein Activities in Vivo

Meyron-Holtz, Esther G.; Ghosh, Manik C.; Rouault, Tracey A.

doi:10.1126/science.1103786

Cited by 225 publications

(208 citation statements)

References 26 publications

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“…Animals that lack IRP1 are unable to repress ferritin synthesis fully in the kidney under conditions of iron deficiency (33), demonstrating that IRP1 contributes significantly to regulation of iron metabolism in the kidney (Figures 5 and 6). In most other tissues, loss of IRP1-binding activity does not lead to misregulation of iron metabolism, because IRP2 levels increase in compensation (33,45). However, in kidney of IRP1Ϫ/Ϫ mice, although IRP2 levels increase in a compensatory manner, as expected, the increase in IRP2 is not sufficient to repress ferritin synthesis completely (Figures 5 and 6).…”

Section: Renal Regulation Of Ferritin and Tfr Expression: Role Of Irosupporting

confidence: 56%

Renal Iron Metabolism

Zhang¹,

Meyron-Holtz²,

Rouault³

2007

Journal of the American Society of Nephrology

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Section: Renal Regulation Of Ferritin and Tfr Expression: Role Of Irosupporting

confidence: 56%

Renal Iron Metabolism

Zhang¹,

Meyron-Holtz²,

Rouault³

2007

Journal of the American Society of Nephrology

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“…The high IRP1 affinity may occur as a consequence of the reduced TBI uptake into and increased iron efflux from Salmonella-infected IFN-c-stimulated macrophages and the formation of NO. In contrast, the relatively low IRP2-binding activity may result from the degradation of IRP2 upon production of NO + , hypoxia or activation of ubiquitin-and non-ubiquitin-mediated pathways, and may thus prevent a compensatory induction of TfR1 expression under these conditions [49][50][51][52]. Changes in cellular oxygen levels under the inflammatory stimuli applied in our experiments may determine the specific contributions of IRP1 and IRP2, respectively, to the regulation of macrophage iron homeostasis in response to S. typhimurium infection and IFN-c stimulation [51].…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, the relatively low IRP2-binding activity may result from the degradation of IRP2 upon production of NO + , hypoxia or activation of ubiquitin-and non-ubiquitin-mediated pathways, and may thus prevent a compensatory induction of TfR1 expression under these conditions [49][50][51][52]. Changes in cellular oxygen levels under the inflammatory stimuli applied in our experiments may determine the specific contributions of IRP1 and IRP2, respectively, to the regulation of macrophage iron homeostasis in response to S. typhimurium infection and IFN-c stimulation [51]. Furthermore, macrophage-derived cytokines including IL-1ß, IL-6 and IL-10 were secreted in substantial amounts by Salmonella-infected cells (details not shown) and may contribute to the regulation of cellular iron homeostasis by non IRP-mediated transcriptional and translational regulation of TfR1 and/or ferritin expression [53][54][55].…”

Section: Discussionmentioning

confidence: 99%

Interferon‐γ limits the availability of iron for intramacrophage Salmonella typhimurium

et al. 2008

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In stimulating effector functions of mononuclear phagocytes, IFN-c is of pivotal importance in host defense against intramacrophage pathogens including salmonellae. As the activity of IFN-c is modulated by iron and since a sufficient availability of iron is essential for the growth of pathogens, we investigated the regulatory effects of IFN-c on iron homeostasis and immune function in murine macrophages infected with Salmonella typhimurium. In Salmonella-infected phagocytes, IFN-c caused a significant reduction of iron uptake via transferrin receptor 1 and resulted in an increased iron efflux caused by an enhanced expression of the iron exporter ferroportin 1. Moreover, the expression of haem oxygenase 1 and of the siderophore-capturing antimicrobial peptide lipocalin 2 was markedly elevated following bacterial invasion, with IFN-c exerting a super-inducing effect. This observed regulatory impact of IFN-c reduced the intracellular iron pools within infected phagocytes, thus restricting the acquisition of iron by engulfed Salmonella typhimurium while concomitantly promoting NO and TNF-a production. Our data suggest that the modulation of crucial pathways of macrophage iron metabolism in response to IFN-c concordantly aims at withdrawing iron from intracellular Salmonella and at strengthening macrophage immune response functions. These regulations are thus consistent with the principles of nutritional immunity. IntroductionHost defense against intracellular microbes such as salmonellae or mycobacteria strongly depends on cell-mediated immunity, a major component of which is characterized by interactions between Th1 cells and macrophages [1]. By secreting Th1 cytokines, particularly IFN-c, antigen-specific Th1 cells activate a plethora of microbicidal mechanisms in infected macrophages. Specifically, in mononuclear phagocytes infected with Salmonella enterica serovar typhimurium (S. typhimurium), IFN-c promotes the internalization of bacteria and stimulates their elimination by various mechanisms including reactive oxygen and nitrogen species (ROS and RNS), generated via NADPH phagocyte oxidase and iNOS, respectively [2][3][4][5]. In Salmonella-infected mice, treatment with recombinant IFN-c increases host survival and decreases bacterial numbers in liver and spleen [6]. Conversely, neutralization of murine IFN-c functions with specific antibodies results in reduced host survival and increased bacterial counts [7]. Eur. J. Immunol. 2008. 38: 1923-1936 Immunity to infection In humans, the central importance of IFN-c for immune response against salmonellae is highlighted by the fact that patients with genetic defects in the IL-12-induced production of IFN-c or in the IFN-c receptor 1 selectively suffer from infections with salmonellae and otherwise weakly pathogenic mycobacteria since their phagocytes fail to eliminate these microbes [8,9]. Iron serves as an essential nutrient for nearly all pathogenic microorganisms, and the expression of iron acquisition systems by infectious agents is associated with their virule...

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“…The IRPs RNA-binding activity is also regulated by iron-independent factors, such as oxidative stress [17], nitric oxide signalling [18], protein phosphorylation [19], hypoxia [20,21], as well as oxalomalic acid, an inhibitor of aconitase/IRP1 [22,23], and virus infection [24]. Among hormones, thyroid hormones regulate post-transcriptionally the synthesis of proteins involved in iron metabolism by affecting IRPs ability to bind to IRE [25].…”

Section: Introductionmentioning

confidence: 99%

Ovariectomy and estrogen treatment modulate iron metabolism in rat adipose tissue

Raso

Irace

Esposito

et al. 2009

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Page 1 of 30A c c e p t e d M a n u s c r i p Graphical AbstractPage 2 of 30 A c c e p t e d M a n u s c r i p t E-mail address: rsantama@unina.it (R. Santamaria). * ManuscriptPage 3 of 30 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 ABSTRACTIron is essential for many biological processes and its deficiency or excess is involved in pathological conditions. At cellular level, the maintenance of iron homeostasis is largely accomplished by the transferrin receptor (TfR)-1 and by ferritin, whose expression is mainly regulated post-transcriptionally by Iron Regulatory Proteins (IRPs).This study examines the hypothesis that modification of serum estrogen levels by ovariectomy and 17β-estradiol (E 2 ) treatment in rats modulate serum iron-status parameters and iron metabolism in adipose tissue. In particular, we evaluated the RNA binding of IRP1 by electrophoretic mobility shift assay and IRP1, ferritin, and TfR-1 expression in adipose tissue by Western blot analysis.Ovariectomy, besides a lowered serum iron and transferrin iron binding capacity, remarkably decreased the binding activity of IRP1 in peritoneal and subcutaneous adipose tissues, and these effects were reversed by E 2 treatment. Moreover, ovariectomy determined a decrease of IRP1 expression, which was significant in subcutaneous adipose tissue. Consistent with IRP1 regulation, an increase of ferritin and a decrease of TfR-1 expression were observed in peritoneal adipose tissue from ovariectomized animals, while the treatment with E 2 reconstituted TfR-1 level. A similar expression profile of TfR-1 was observed in subcutaneous adipose tissue, where ferritin level did not change in ovariectomized animals, and was increased after E 2 treatment.Our results indicate that estrogen level changes can regulate the binding activity of the IRP1, and consequently ferritin and TfR-1 expression in adipose tissue, suggesting a relationship among serum and tissue iron parameters, estrogen status and adiposity.

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Mammalian Tissue Oxygen Levels Modulate Iron-Regulatory Protein Activities in Vivo

Cited by 225 publications

References 26 publications

Renal Iron Metabolism

Renal Iron Metabolism

Interferon‐γ limits the availability of iron for intramacrophage Salmonella typhimurium

Ovariectomy and estrogen treatment modulate iron metabolism in rat adipose tissue

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