Interaction of transferrin with iron‐loaded rat peritoneal macrophages

Saito, K; Nishisato, Takuji; Grasso, Joseph A.; Aisen, Philip

doi:10.1111/j.1365-2141.1986.tb02930.x

Cited by 65 publications

(38 citation statements)

References 20 publications

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“…It is likely that ferrocene initially gains access essentially to parenchymal and thereafter to reticuloendothelial cells where its iron is incorporated into ferritin and subsequently haemosiderin, which remains essentially within the cells. In contrast, iron dextran is probably taken up by macrophages, where its iron is stored only briefly before it is released to the circulation in the form of macrophage ferritin [27,281, which can furnish its iron to apotransferrin [27]. Some of the macrophage ferritin may also be taken up by ferritin receptors on hepatocytes [29], within which it is degraded in lysosomes and its iron is released and reincorporated into hepatocyte femtin [30].…”

Section: Discussionmentioning

confidence: 99%

Control of cellular iron homeostasis by iron‐responsive elements in vivo

Ward

Kühn²,

Kaldy³

et al. 1994

European Journal of Biochemistry

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It has recently been proposed that cellular iron homeostasis in mammalian cells is regulated at the post-transcriptional level by the reciprocal control of transferrin receptor and fenitin mRNA expression via an iron-regulatory factor. This iron-regulatory factor has been shown to be a cytoplasmic aconitase which can bind to iron-responsive elements in the corresponding mRNAs with greater or lesser affinity as a function of the iron status of the cell. In the present study, we show that in vivo the affinity of iron-regulatory factor for iron-responsive elements in liver reflects the long-term iron status of the tissue in animal models for iron overloading and iron deficiency, when combined with altered transferrin saturation and serum iron levels. In contrast hepatic iron overload achieved without altering such haematopoeitic indices, had a less pronounced effect. In both spleen and heart, the affinities of iron-regulatory factor changed in parallel with both altered iron status and haematological markers. In brain and duodenum, there were no consistent changes in ironregulatory-factor activity with iron loading or depletion. Iron-regulatory-factor activity in kidney responded in an as yet unexplained manner.Iron is an essential element for the growth, differentiation and well-being of most living organisms [l]. It is therefore of paramount importance to understand at the molecular, cellular and whole-organism level how iron homeostasis is regulated. Cellular iron homeostasis can be defined as the mechanisms whereby the intracellular concentration of the metal ion is maintained at a level adequate for the cell's requirements, but not sufficiently high to cause toxic effects. This is achieved by regulating the uptake of the metal ion in concert with its intracellular utilisation, storage and eventual externalization. It has been suggested that the expression of several key proteins of iron metabolism is regulated by intracellular iron levels [2-61. The post-transcriptional regulation of the iron-storage protein ferritin, the erythroid 5-aminolaevulinate synthase (AlS) and the transfenin receptor operate at the level of mRNA. All H-chain and L-chain ferritin mRNAs [3, 7, binds tightly to the IRE of transferrin-receptor mRNA, thereby ensuring its protection against nuclease digestion [20] and translation of the transferrin receptor, thus enhancing the uptake of iron by the cell. The same iron-depleted form of IRF binds strongly to the femtin and A1S mRNAs and thus blocks the biosynthesis of ferritin erythroid AlS. When cells are replete in iron the IRF binds poorly to femtin and erythroid AIS mRNAs ensuring their expression, and dissociates from the transfenin-receptor mRNA ensuring that it will be degraded by cellular nucleases. Thus, the model implies a coordinate regulation at the level of translation of mRNAs for ferritin and erythroid AlS, on the one hand, and transferrin receptor on the other.The IRF has been clearly shown to be a cytosolic aconitase which, in its active 4Fe-4S form, has a turnover number s...

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Section: Discussionmentioning

confidence: 99%

Control of cellular iron homeostasis by iron‐responsive elements in vivo

Ward

Kühn²,

Kaldy³

et al. 1994

European Journal of Biochemistry

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“…Likewise, the marked elevation of plasma Cp during the anemia of inflammation, when reticuloendothelial cell iron stores are elevated, remains paradoxical (15). The requirement for apotransferrin in macrophage iron release in vitro is also controversial; several investigators have shown a lack of stimulation by apotransferrin (16,17), whereas others have found a stimulatory effect (18). In fact, under some circumstances, Cp may enhance iron uptake by cells, possibly by a trivalent cation transporter on the cell surface (19 -21).…”

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confidence: 99%

Role of Ceruloplasmin in Macrophage Iron Efflux during Hypoxia

Sarkar

Seshadri

Tripoulas

et al. 2003

Journal of Biological Chemistry

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The reticuloendothelial system has a central role in erythropoiesis and iron homeostasis. An important function of reticuloendothelial macrophages is phagocytosis of senescent red blood cells. The iron liberated from heme is recycled for delivery to erythrocyte precursors for a new round of hemoglobin synthesis. The molecular mechanism by which recycled iron is released from macrophages remains unresolved. We have investigated the mechanism of macrophage iron efflux, focusing on the role of ceruloplasmin (Cp), a copper protein with a potent ferroxidase activity that converts Fe 2؉ to Fe 3؉ in the presence of molecular oxygen. As shown by others, Cp markedly increased iron binding to apotransferrin at acidic pH; however, the physiological significance of this finding is uncertain because little stimulation was observed at neutral pH. Introduction of a hypoxic atmosphere resulted in marked Cp-stimulated binding of iron to apotransferrin at physiological pH. The role of Cp in cellular iron release was examined in U937 monocytic cells induced to differentiate to the macrophage lineage. Cp added at its normal plasma concentration increased the rate of 55 Fe release from U937 cells by about 250%. The stimulation was absolutely dependent on the presence of apotransferrin and hypoxia. Cp-stimulated iron release was confirmed in mouse peritoneal macrophages. Stimulation of iron release required an intracellular "labile iron pool" that was rapidly depleted in the presence of Cp and apotransferrin. Ferroxidase-mediated loading of iron into apotransferrin was critical for iron release because ferroxidasedeficient Cp was inactive and because holotransferrin could not substitute for apotransferrin. The extracellular iron concentration was critical as shown by inhibition of iron release by exogenous free iron, and marked enhancement of release by an iron chelator. Together these data show that Cp stimulates iron release from macrophages under hypoxic conditions by a ferroxidasedependent mechanism, possibly involving generation of a negative iron gradient.

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“…The only possibility that this reaction could take place in vivo would be iron release from serum ferritin to transferrin. Saito et al [9] have observed release of iron in a ferritin-like form by cultured rat macrophage after ingestion of 59Fe-labelled erythrocytes. They have also found that much of the initial labelled iron was bound to apotransfer- [17].…”

Section: Discussionmentioning

confidence: 99%

“…Although apotransferrin receptors have been found recently on rat macrophages [8], the presence of apotransferrin does not appear to be essential for the excretion of iron by these cells [9]. It thus appears that the inverse 'transferrin cycle' [10,11] would probably not be appropriate to explain the mechanism of intracellular iron mobilization.…”

Section: Introductionmentioning

confidence: 94%

Iron transfer from ferritin to transferrin

Jin

Crichton

1987

FEBS Letters

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The transfer of iron from 59Fe-labelled human spleen ferritin to human apotransferrin occurs in the absence of either reducing or chelating agents. The reaction is first order with respect to ferritin and zero order to apotransferrin. The transfer is enhanced by low-Mr substances from human serum such as ascorbate, citrate, bicarbonate and lactate. A mixture of the four molecules at their normal physiological concentrations can increase the iron exchange to the same extent as that observed with an ultrafiltrate of serum. A pathway of intracellular iron mobilization is considered.

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Interaction of transferrin with iron‐loaded rat peritoneal macrophages

Cited by 65 publications

References 20 publications

Control of cellular iron homeostasis by iron‐responsive elements in vivo

Control of cellular iron homeostasis by iron‐responsive elements in vivo

Role of Ceruloplasmin in Macrophage Iron Efflux during Hypoxia

Iron transfer from ferritin to transferrin

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