Control of Transferrin Receptor Expression via Nitric Oxide-mediated Modulation of Iron-regulatory Protein 2

Kim, Sangwon; Ponka, Prem

doi:10.1074/jbc.274.46.33035

Cited by 89 publications

(124 citation statements)

References 44 publications

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“…ϩ caused a significant decrease in IRP-2 binding to the IRE, associated with a dramatic decrease in TfR mRNA levels in RAW 264.7 (44). Similar changes occur in RAW 264.7 cells following their treatment with LPS and IFN-␥ (see Fig.…”

Section: Inhibitors Of Inos Prevent Irp-2 Degradation and Attenuate Tsupporting

confidence: 58%

“…The decrease in IRP-2 binding/levels was associated with a dramatic decrease in TfR mRNA. Importantly, these changes occurred at a time at which IRE binding activity of IRP-1 was not yet decreased by NO ϩ treatment (43,44), indicating that IRP-2 alone plays a crucial role in controlling TfR mRNA levels. In this study, we found that stimulation of RAW 264.7 cells with IFN-␥ and LPS caused a strong reduction of IRP-2 activity, accompanied by a dramatic drop in TfR mRNA levels, changes similar to those occurring in NO ϩ -treated RAW 264.7 cells (44).…”

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confidence: 95%

“…On the other hand, we have concluded that treatment of K562 cells with an NO ϩ donor resulted in S-nitrosylation of critical thiol groups that may prevent binding of IRP-1 to the IRE, leading to TfR mRNA degradation (32). Our more recent study yielded data indicating that IRP-2 may also be a very important and unexpected target for NO ϩ (43,44). We found that a 1-h exposure of RAW 264.7 cells (a murine macrophage cell line) to a NO ϩ generator caused a significant decrease in IRP-2 binding to the IRE, followed by IRP-2 degradation, probably in proteasomes.…”

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confidence: 96%

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Effects of Interferon-γ and Lipopolysaccharide on Macrophage Iron Metabolism Are Mediated by Nitric Oxide-induced Degradation of Iron Regulatory Protein 2

Kim

Ponka

2000

Journal of Biological Chemistry

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138

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Iron regulatory proteins (IRP-1 and IRP-2) control the synthesis of transferrin receptors (TfR) and ferritin by binding to iron-responsive elements, which are located in the 3-untranslated region and the 5-untranslated region of their respective mRNAs. Cellular iron levels affect binding of IRPs to iron-responsive elements and consequently expression of TfR and ferritin. Moreover, NO ⅐ , a redox species of nitric oxide that interacts primarily with iron, can activate IRP-1 RNA binding activity resulting in an increase in TfR mRNA levels. Recently we found that treatment of RAW 264.7 cells (a murine macrophage cell line) with NO ؉ (nitrosonium ion, which causes S-nitrosylation of thiol groups) resulted in a rapid decrease in RNA binding of IRP-2 followed by IRP-2 degradation, and these changes were associated with a decrease in TfR mRNA levels (Kim, S., and Ponka, P. Macrophages stimulated by cytokines, such as interferon-␥ (IFN-␥), 1 or microbial components, such as lipopolysaccharide (LPS), take part in the nonspecific resistance against pathogens (1). It is now well established that cytostatic and cytotoxic effects of murine macrophages are caused in part by nitric oxide (NO) produced enzymatically by the stepwise oxidation of L-arginine to NO and L-citrulline (2, 3). The cytotoxic function of NO requires that it is produced in relatively large quantities in macrophages and some other cells and this is accomplished by inducible NO synthase (iNOS) (3). Many of the cytotoxic effects of NO can be explained by its reactivity with iron in the active sites of critically important molecules such as mitochondrial aconitase, ribonucleotide reductase, and the [Fe-S] proteins of the mitochondrial respiratory system (reviewed in Refs. 3 and 4). Moreover, the identification of the [4Fe-4S] cluster of mitochondrial aconitase as a target susceptible to inactivation by NO suggested that NO may also be involved in the regulation of iron regulatory protein (IRP)-1, which is closely related to mitochondrial aconitase (5-7). Although many actions of NO are mediated by its binding to either non-heme or heme iron (8), this metal is not the only target for NO. The oxidized form of NO, the nitrosonium ion (NO ϩ ), can S-nitrosylate proteins via their thiol groups, a modification that may have important regulatory functions (9 -14).IRP-1 and IRP-2 are cytoplasmic proteins known to interact with specific nucleotide sequences, known as iron-responsive elements (IREs) (reviewed in Refs. 15-19), which are located in the 5Ј-untranslated region of ferritin mRNA (20) and the 3Ј-untranslated region of transferrin receptor (TfR) mRNA (21). The interactions of IRPs with IREs control cellular iron metabolism in the following manner: When cellular iron becomes limiting, IRP-2 is present in the cytosol, and the IRP-1 is recruited into the high affinity binding state. The binding of IRPs to the IRE in the 5Ј-untranslated region of the ferritin mRNA blocks the translation of ferritin, whereas an association of IRPs with IREs in the 3Ј-untranslated r...

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Section: Inhibitors Of Inos Prevent Irp-2 Degradation and Attenuate Tsupporting

confidence: 58%

mentioning

confidence: 95%

mentioning

confidence: 96%

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Effects of Interferon-γ and Lipopolysaccharide on Macrophage Iron Metabolism Are Mediated by Nitric Oxide-induced Degradation of Iron Regulatory Protein 2

Kim

Ponka

2000

Journal of Biological Chemistry

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138

113

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“…Iron-regulatory Protein Binding Activity Assay-Iron-regulatory protein (IRP) binding was determined using a band shift assay as described previously (23). Briefly, 5-10 million cells were washed with ice-cold phosphate-buffered saline and lysed at 4°C in 80 l of lysis buffer (10 mM HEPES, pH 7.5, 3 mM MgCl 2 , 40 mM NaCl, 5% glycerol, 1 mM dithiothreitol, and 0.2% Nonidet P-40).…”

Section: Methodsmentioning

confidence: 99%

Non-heme Induction of Heme Oxygenase-1 Does Not Alter Cellular Iron Metabolism

Sheftel

Kim

Ponka

2007

Journal of Biological Chemistry

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The catabolism of heme is carried out by members of the heme oxygenase (HO) family. The products of heme catabolism by HO-1 are ferrous iron, biliverdin (subsequently converted to bilirubin), and carbon monoxide. In addition to its function in the recycling of hemoglobin iron, this microsomal enzyme has been shown to protect cells in various stress models. Implicit in the reports of HO-1 cytoprotection to date are its effects on the cellular handling of heme/iron. However, the limited amount of uncommitted heme in non-erythroid cells brings to question the source of substrate for this enzyme in non-hemolytic circumstances. In the present study, HO-1 was induced by either sodium arsenite (reactive oxygen species producer) or hemin or overexpressed in the murine macrophage-like cell line, RAW 264.7. Both of the inducers elicited an increase in active HO-1; however, only hemin exposure caused an increase in the synthesis rate of the iron storage protein, ferritin. This effect of hemin was the direct result of the liberation of iron from heme by HO. Cells stably overexpressing HO-1, although protected from oxidative stress, did not display elevated basal ferritin synthesis. However, these cells did exhibit an increase in ferritin synthesis, compared with untransfected controls, in response to hemin treatment, suggesting that heme levels, and not HO-1, limit cellular heme catabolism. Our results suggest that the protection of cells from oxidative insult afforded by HO-1 is not due to the catabolism of significant amounts of cellular heme as thought previously.In the average adult, at equilibrium ϳ2 million red blood cells are being turned over every second. In a day, this process requires about 25 mg of iron (Fe) to be recycled from the hemoglobin of effete erythrocytes. Heme oxygenase 1 (HO-1) 2 is the enzyme responsible for catabolizing the heme from senescent red blood cells to release Fe, as well as equimolar amounts of carbon monoxide (CO) and biliverdin, for its eventual reuse in erythropoiesis. Another noninducible isoform of heme oxygenase with heme catabolic properties similar to HO-1, HO-2 is present in substantial levels primarily in the central nervous system and testes (1, 2). Although the heme-degrading function of HO has been known since the 1960s (3, 4), only recently has it been shown that heme oxygenases may be involved in cytoprotection against cellular stresses (for review see Camara and Soares (5), Abraham and Kappas (6), Otterbein et al. (7), and Ryter et al. (8)). This newer discovery of the potential of these enzymes as a tissue defense mechanism has spawned a flurry of studies by numerous groups who have shown by several different approaches that induction or overexpression of heme oxygenase 1 can protect tissues from various insults, including oxidative stress and immune system attack.The precise mechanism by which HO-1 mediates its protective function remains controversial. Breakdown of heme being the only known reaction catalyzed by the enzyme, extensive research has alleged that one or mo...

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“…In particular, the role of transferrin receptor 1 (TfR1), which mediates transferrinbound iron uptake [1][2][3], is not fully understood. Studies of murine and human reticuloendothelial cells [8,[17][18][19] have shown that, despite an early NF-kB and HIF-1-dependent transcriptional upregulation [20], TfR1 expression is post-transcriptionally downmodulated by exposure to inflammatory stimuli for 10-24 h, an effect that would impair a major iron uptake mechanism. However, inflammation may increase the uptake of other forms of iron.…”

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confidence: 99%

Differential regulation of iron homeostasis during human macrophage polarized activation

et al. 2010

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Iron metabolism in inflammation has been mostly characterized in macrophages exposed to pathogens or inflammatory conditions, mimicked by the combined action of LPS and IFN-c (M1 polarization). However, macrophages can undergo an alternative type of activation stimulated by Th2 cytokines, and acquire a role in cell growth and tissue repair control (M2 polarization). We characterized the expression of genes related to iron homeostasis in fully differentiated unpolarized (M0), M1 and M2 human macrophages. The molecular signature of the M1 macrophages showed changes in gene expression (ferroportin repression and H ferritin induction) that favour iron sequestration in the reticuloendothelial system, a hallmark of inflammatory disorders, whereas the M2 macrophages had an expression profile (ferroportin upregulation and the downregulation of H ferritin and heme oxygenase) that enhanced iron release. The conditioned media from M2 macrophages promoted cell proliferation more efficiently than those of M1 cells and the effect was blunted by iron chelation. The role of ferroportin-mediated iron release was demonstrated by the absence of differences from the media of macrophages of a patient with loss of function ferroportin mutation. The distinct regulation of iron homeostasis in M2 macrophages provides insights into their role under pathophysiological conditions. Key words: Immune system . Iron . Polarized macrophages IntroductionMacrophages play a critical role in body iron homeostasis by recovering iron from old red blood cells and returning it to the circulation for binding to transferrin, which delivers the metal to the cells that need it for various functions, thus contributing more than 80% to daily iron turnover [1][2][3].Iron retention in the reticuloendothelial system is the main response of body iron homeostasis to inflammation and is regarded as a host's attempt to withhold iron from the invading pathogens [4]. This restricts iron availability for erythroid progenitor cells and may contribute toward causing the common condition of inflammation-related anaemia [1,5,6]. Increased iron retention within inflammatory macrophages is due to increased iron uptake and decreased iron export [7], and is favoured by the induction of the iron storage protein ferritin (Ft) [8,9]. The blockade of macrophage iron release is mainly due to the interaction between the acute phase protein hepcidin and the iron exporter ferroportin (Fpn) [1][2][3], as the increase in circulating hepcidin triggered by inflammatory cytokines causes the internalization and degradation of Fpn [10], the exporter of non-heme iron [11], thus blocking iron release from macrophages.Macrophage Fpn is also negatively regulated at transcriptional and post-transcriptional levels by inflammatory mediators [12][13][14]. It is still unknown whether the inflammatory response affects the feline leukemia virus, subgroup C, receptor that exports heme from macrophages [15] and whether the heme transporter HRG1 proteins play a role in macrophage iron metabolism [16]. O...

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Control of Transferrin Receptor Expression via Nitric Oxide-mediated Modulation of Iron-regulatory Protein 2

Cited by 89 publications

References 44 publications

Effects of Interferon-γ and Lipopolysaccharide on Macrophage Iron Metabolism Are Mediated by Nitric Oxide-induced Degradation of Iron Regulatory Protein 2

Effects of Interferon-γ and Lipopolysaccharide on Macrophage Iron Metabolism Are Mediated by Nitric Oxide-induced Degradation of Iron Regulatory Protein 2

Non-heme Induction of Heme Oxygenase-1 Does Not Alter Cellular Iron Metabolism

Differential regulation of iron homeostasis during human macrophage polarized activation

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