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PubMed2005

Staphylococcus aureus siderophore-mediated iron-acquisition system plays a dominant and essential role in the utilization of transferrin-bound iron.

Staphylococcus aureus is known to be capable of utilizing transferrin-bound iron, via both siderophore- and transferrin-binding protein (named IsdA)-mediated iron-acquisition systems. This study was designed in order to determine which iron-acquisition system plays the essential or dominant role with respect to the acquisition of iron from human transferrin, in the growth of S. aureus. Holotransferrin (HT) and partially iron-saturated transferrin (PT), but not apotransferrin (AT), were found to stimulate the growth of S. aureus. S. aureus consumed most of the transferrin-bound iron during the exponential growth phase. Extracellular proteases were not, however, involved in the liberation of iron from transferrin. Transferrin-binding to the washed whole cells via IsdA was not observed during the culture. The expression of IsdA was observed only in the deferrated media with AT, but not in the media supplemented with PT or HT. In contrast, siderophores were definitely produced in the deferrated media with PT and HT, as well as in the media supplemented with AT. The siderophores proved to have the ability to remove iron directly from transferrin, but the washed whole cells expressing IsdA did not. In the bioassay, the growth of S. aureus on transferrin-bound iron was stimulated by the siderophores alone. These results demonstrate that the siderophore-mediated iron-acquisition system plays a dominant and essential role in the uptake of iron from transferrin, whereas the IsdA-mediated iron-acquisition system may play only an ancillary role in the uptake of iron from transferrin.

Bacterial Transferrin Receptor Complex↗
PubMed1986

Evidence that transferrin may function exclusively as an iron donor in promoting lymphocyte proliferation.

In order to distinguish between a requirement for iron and a possible additional requirement for the iron-binding protein transferrin per se, the ability of mouse lymphocytes to proliferate in response to concanavalin A has been investigated. Cells proliferated well when cultured in medium containing 5% fetal calf serum, but if iron-free mouse or human transferrins were added, proliferation was inhibited by greater than 80%, whereas the same transferrins saturated to 30% with iron enhanced proliferation by 40-70%. In serum-free medium, proliferation was greater in the presence of 30% iron-saturated transferrin than when the protein was saturated only to 10%. Addition of Mn3+ to the latter, to bring the total metal saturation to 30%, gave no improvement in proliferation. Lymphocytes took up iron preferentially when transferrin containing both iron and manganese was present in the culture medium. The degree of proliferation in serum-free medium in the presence of a variant of human transferrin with abnormal iron-binding and receptor-binding properties was almost identical to that when normal human transferrin was used. Finally, when a monoclonal antibody to the mouse transferrin receptor and iron-nitriotriacetate were substituted for iron-transferrin in serum-free medium, proliferation was reduced by greater than 95%. These results strongly suggest that transferrin promotes lymphocyte proliferation solely as a result of its iron-donating properties, and that an additional role such as the provision of a proliferation-inducing membrane signalling event following interaction with the transferrin receptor seems unlikely.

Animals↗
PubMed1981

Physical characterization of the transferrin receptor in human placentae.

The physical properties and binding characteristics of the solubilized transferrin receptor isolated from the placental brush-border membrane of a human trophoblast cell were investigated. The receptor protein was isolated from solubilized 125I-labeled membranes by immunoprecipitation with anti-human transferrin in the presence of saturating amounts of human transferrin. Gel filtration on acrylamide agarose (AcA-22) at 23 degrees C in the absence of transferrin indicates the transferrin receptor has a Stokes radius of 4.6 nm. In the presence of transferrin, the Stokes radius of the receptor shifts to 6.3 nm. Sucrose density centrifugation studies indicate that it has a sedimentation coefficient of 9.8 S in the absence of transferrin and 11.2 S in the presence of transferrin. The molecular weight for the transferrin free receptor is calculated to be 213,000. Upon incubation with transferrin, it increases to 364,000. This is consistent with the idea that the active form of the solubilized receptor is a dimer and the dimer is in turn capable of binding two transferrin molecules.

Cell Membrane↗
PubMed1984

Transferrin receptor function in hereditary hemochromatosis.

The binding of 125I-diferric transferrin to cultured skin fibroblasts and phytohemagglutinin-stimulated lymphocytes was studied in cells derived from individuals homozygous for hereditary hemochromatosis and from normal individuals. Receptors with a high affinity for diferric transferrin were present on all cells. Transferrin receptor number decreased by more than 50% when fibroblasts from both normal and hemochromatotic subjects were maintained in iron-supplemented medium. The number of transferrin receptors expressed by normal and hemochromatotic lymphocytes after mitogen stimulation in iron-supplemented media was less than 50% that of lymphocytes which were mitogen stimulated in standard medium. No change in the affinity of the receptors for diferric transferrin was seen in cells maintained in iron-supplemented medium. Competition experiments in the presence of deferoxamine suggested that the transferrin receptors of fibroblasts and mitogen-stimulated lymphocytes have a 70- to 100-fold higher affinity for diferric transferrin than for apotransferrin. No differences in the properties of transferrin receptors were found between patients with hereditary hemochromatosis and normal individuals. Although transferrin binding decreases when cells are exposed to high levels of iron in the medium, the failure to totally abolish transferrin binding to the receptor suggests that the concentration of diferric transferrin to which cells are exposed may be a major determinant of cellular iron loading in hereditary hemochromatosis.

Cells, Cultured↗
PubMed1996

Immunohistochemical localization of intraneuronal transferrin receptor immunoreactivity in the adult mouse central nervous system.

Iron is essential for a variety of intracellular functions. Accordingly, the transfer of iron from blood to brain is vital for normal brain function. In the CNS, the receptor for iron-transferrin is generally accepted to be located in endothelial cells, whereas its occurrence in other cell types is less well established. I have investigated the distribution of the transferrin receptor in the adult mouse central nervous system by immunohistochemistry by using a monoclonal antibody raised against the transferrin receptor protein. Immunoreactive cell types comprised brain capillary endothelial cells, excluding those of circumventricular organs, and choroid plexus epithelial cells. Moreover, transferrin receptor immunoreactivity was detected intraneuronally in several brain regions without access to peripheral blood. The immunoreactive cell bodies were mainly confined to the cerebral cortex, hippocampus, habenular nucleus, red nucleus, substantia nigra, pontine nuclei, reticular formation, several cranial nerve nuclei, deep cerebellar nuclei, and cerebellar cortex. Transferrin receptor immunoreactivity was not detected in astrocytes, oligodendrocytes, or microglial cells. The occurrence of transferrin receptors at brain-barrier sites, i.e., the brain endothelium and choroid plexus epithelium, and the presence of the receptors intraneuronally are in accordance with the generally held belief that iron is released from liver transferrin and transported through capillaries and the choroid plexus into the brain interstitium. Subsequently, iron may be linked to brain transferrin synthesized within oligodendrocytes and choroid plexus epithelial cells followed by a concomitant uptake of iron-transferrin in neurons expressing transferrin receptors. The clinical importance of the intraneuronal transferrin receptor expression is discussed.

Animals↗
PubMed1992

The perfused liver is capable of producing all transferrin glycan variants found in the sera of intact rats.

The single oligosaccharide attachment in rat transferrin exhibits marked structural microheterogeneity. In this study we examined whether all microheterogeneous forms of rat transferrin found in plasma are derived from a single organ, such as the liver. To this end we analyzed the glycans of rat transferrin synthesized by the isolated perfused rat liver by a method established earlier for rat transferrin isolated from rat plasma. Our observations provide evidence that the liver can and does produce all variant rat transferrin glycans present in plasma. However, this discovery does not preclude the possibility that extrahepatic sources with an active rat transferrin gene may contribute to the circulation rat transferrin molecules, which bear glycan variants identical to those made by the liver. The glycan spectra of rat transferrin in plasma and in liver perfusate compared closely with each other in a quantitative sense. Nevertheless, rat transferrin in the perfusate was sialylated to a lesser extent and fucosylated to a greater extent than rat transferrin in plasma. These differences could not be eliminated by supplementation of the medium with insulin, dexamethasone, pyruvate and adenine or adenosine either alone or in combinations, nor could it be eliminated by use of a fluorocarbon O2 carrier. In contrast, epidermal growth factor normalized both parameters. The pH of the perfusing medium also influenced sialylation and fucosylation in such a way that higher pH brought these parameters closer to their values in plasma rat transferrin. Lower pH, on the other hand, reduced sialylation and left the fucosylation index unchanged.

Animals↗
PubMed1987

Transferrin-receptor interaction and iron uptake by reticulocytes of vertebrate animals--a comparative study.

Transferrin-receptor interactions and iron uptake were studied in eleven different species of vertebrate animals (3 eutherian mammals, 3 marsupials, 2 reptiles and 1 bird, amphibian and bony fish). In the initial experiments it was shown that the uptake of transferrin-bound iron by immature erythroid cells from marsupial and reptilian species occurs by receptor-mediated endocytosis as in other vertebrate animals. Reticulocytes were incubated with 125I-59Fe-labelled transferrins from heterologous species and the results for iron and transferrin uptake compared with those obtained with the homologous protein. Cells from eutherian mammals were able to take up transferrin and iron from other eutherians and from the bob-tailed lizard but not from marsupials and other submammalian species. With marsupials and reptiles a similar specificity was observed, and the marsupial cells could also utilize chicken transferrin but not vice versa. The results were extended by performing competition experiments in which the cells were incubated with radiolabelled homologous transferrin in the presence of increasing concentrations of non-radioactive heterologous transferrins. From the ability of the heterologous proteins to inhibit uptake of the homologous protein relative association constants (Ka1) for the transferrin-receptor interactions could be calculated. These Ka1 values reflected the patterns observed in the first series of experiments. These studies demonstrate that, although specificity exists in transferrin-receptor interactions throughout the range of vertebrate animals, in several instances reactivity between widely divergent species is also observed. Hence, structural similarities have been maintained throughout evolution. Nevertheless, no evidence of interaction between transferrin and its receptor from the two divisions of the Mammalia, the eutherians and the marsupials, was observed.

Animals↗
PubMed1988

Transferrin and iron requirements of embryonic mesoderm cells cultured in hydrated collagen matrices.

Very early embryonic mesoderm cells were taken from the primitive streak-stage chick embryo and cultured in a matrix of type I collagen in the presence of serum. Previous work has shown that under these conditions cells do not leave the explant and move in the collagen in the absence of supplemented avian transferrin. Cells explanted onto tissue culture plastic in the presence of serum do not require this transferrin supplement. These observations were investigated further by culturing cells in collagen in the presence of the lipophilic iron chelator, ferric pyridoxal isonicotinoyl hydrazone (FePIH), which can replace transferrin as an iron-delivery agent. Under conditions in which FePIH could effectively stimulate chick embryo myoblast growth, no such long-term stimulation was obtained with the early mesoderm cells in collagen. This suggested that for mesoderm cells, FePIH could not replace transferrin. Antibody to the transferrin receptor and to transferrin itself inhibited growth of myoblasts in collagen and on plastic, and of mesoderm cells in collagen. Mesoderm cells on plastic, however, were refractory to the presence of the antibody directed to the receptor and seemed to show a low dependency on transferrin-delivered iron under these conditions, inasmuch as antiserum to transferrin itself only caused a partial inhibition of outgrowth. The results suggest that mesoderm cells in collagen require transferrin for both iron uptake and for another unspecified function. It is consistent with the results to propose that transferrin binding might modulate the cells' attachment to collagen, thus influencing outgrowth. The distribution of the actin cytoskeleton in mesoderm cells actively migrating in collagen, such as in the presence of transferrin, suggests a stronger attachment to the collagen than nonmigrating cells.

Actins↗
PubMed1998

The competition between transferrins labeled with 59Fe, 65Zn, and 54Mn for the binding sites on lactating mouse mammary gland cells.

Using a homologous competition of 54Mn-transferrin with Mn-transferrin and 65Zn-transferrin with Zn-transferrin, it was found that on the plasma membrane of lactating mouse mammary gland cells there are receptor binding Mn-transferrin and Zn-transferrin. The heterologous competition between labeled and nonlabeled Fe-transferrin, Mn-transferrin and Zn-transferrin, as well as almost equal affinity constants of cellular receptors toward the three metals by competition of Fe-transferrin suggests that one and the same receptor accepts all three metals from the transferrin molecule. The cell receptors therefore possess a polymetal binding function. A model and a mechanism for regulation of the transport metal flow toward the mammary gland cell acting like "automated switching over" are proposed.

Animals↗
PubMed1984

Transferrin receptors and iron utilization in DMSO-inducible and -uninducible Friend erythroleukemia cells.

Dimethylsulfoxide (DMSO) induces hemoglobin synthesis and erythroid differentiation of Friend erythroleukemia cells in vitro. Induction is accompanied by increased transferrin-binding activity which is necessary for the cellular acquisition of iron from transferrin for hemoglobin synthesis. There are Friend cell variants in which hemoglobin synthesis is not induced by DMSO unless exogenous hemin is also present. In this study we have compared the inducibility of transferrin receptors and iron incorporation in DMSO-inducible (745) and -uninducible (M-18 and TG-13) Friend cell lines. Cellular transferrin-binding sites were estimated by Scatchard analysis of data obtained from specific binding of [125I]transferrin by the cells. Our results show that unlike 745, DMSO treatment of the variant cell lines M-18 and TG-13 does not result in increased transferrin-binding activity. The number of transferrin-binding sites and the rate of iron uptake is similar in uninduced 745 and DMSO-treated M-18 and TG-13 cells. Although exposure of M-18 cells to DMSO and hemin induces hemoglobinization, this treatment does not cause induction of transferrin receptors. These results indicate that the primary defect in M-18 cells may be the uninducibility of transferrin receptors. We have also shown that exposure of 745 cells to hemin during DMSO treatment prevents the induction of transferrin receptors, suggesting that hemin may control the expression of transferrin receptors in erythroid cells.

Animals↗
PubMed1991

Distribution and number of transferrin receptors in Parkinson's disease and in MPTP-treated mice.

Transferrin is a glycoprotein that functions primarily to deliver iron to the cell. Recent studies suggest that the transferrin receptor mediates the intracellular delivery and transport of iron bound to transferrin in the CNS. Iron-catalyzed free radical generation has been proposed as a possible cause of nigral cell death in Parkinson's disease. Our hypothesis is that abnormal iron handling by the transferrin receptor may contribute to the formation of free radical species which catalyze the lipid peroxidation of nigral cell membranes. We have assessed the number of transferrin receptors on membrane fractions prepared from the human striatum from control subjects and patients with Parkinson's disease. Equilibrium-binding studies demonstrated a reversible, saturable, and high-affinity transferrin binding site (KD = 3 nM) in human brain membranes. Regional binding assays indicate that the number of transferrin receptors in the putamen was reduced significantly in Parkinson's disease. The density of transferrin receptors was unaltered in membranes prepared from the caudate nuclei and the globus pallidus. To address the possibility that transferrin receptors are located on dopaminergic terminals, we have examined the distribution and number of transferrin receptors in the striatum of MPTP-treated mice using in vitro autoradiographic methods. In these experiments, the loss of dopaminergic terminals in the striatum was visualized by differential [3H]mazindol uptake site autoradiography. A marked reduction in the density of both transferrin receptors and [3H]mazindol binding sites was observed in the mouse striatum 7 days post-MPTP treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1983

Studies on the forms of iron-transferrin released from rabbit reticulocytes.

Measurement of the distribution of the four species of transferrin, viz, apotransferrin, diferric transferrin and the two monoferric transferrin, before and after incubation of iron-rich rabbit transferrin with rabbit reticulocytes showed that not all transferrin released from the cells were in the form of apotransferrin. Instead, a mixture of all four species of the protein was released with apotransferrin and C-terminal monoferric transferrin being the major fractions. The buffer solution containing 125I-labelled transferrin showed a continuous gain in percentages in apotransferrin and C-terminal monoferric transferrin after each incubation with reticulocytes. The N-terminal monoferric transferrin, however, remained unchanged suggesting that in the process of transferrin uptake by cells, the diferric transferrin releases its iron from the acid-labile site at N-domain first before the other iron from the acid-stable site.

Animals↗
PubMed1993

Production of N-terminal and C-terminal human serum transferrin in Escherichia coli.

The elucidation of the relationship of the structure of human serum transferrin to its iron-binding activity and the delineation of the interactions between transferrin and its receptor will require the construction and production of site-specific mutants of human serum transferrin to test the importance of specific structural motifs to the functions of transferrin. The N-terminal domain of transferrin has been previously produced in BHK cells, but the production of the C-terminal domain of transferrin has never been reported. The amino-terminal and carboxyl-terminal half-molecules of human serum transferrin have been cloned into the T7 expression vector pET11a. Contrary to previous reports, nTf and cTf can be easily produced in E. coli. The plasmids produce 38-kDa proteins that are approximately the sizes predicted for N-terminal and C-terminal half-molecules of transferrin, and both proteins react with anti-human serum transferrin antibodies. It is estimated that nTf represents 30-40% of total cellular protein after induction, while cTf represents less than 5% of total cellular protein. This demonstrates that recombinant forms of human serum transferrin can be produced in E. coli and suggests that it will be possible to use a bacterial system to produce other structural variants of transferrin.

Base Sequence↗
PubMed1988

Non-transferrin donors of iron for heme synthesis in immature erythroid cells.

The mechanism of iron uptake from several iron-containing compounds by transferrin-depleted rabbit reticulocytes and mouse spleen erythroid cells was investigated. Iron complexes of DL-penicillamine, citrate and six different aroyl hydrazones may be utilized by immature erythroid cells for hemoglobin synthesis, although less efficiently than iron from transferrin. HTF-14, a monoclonal antibody against human transferrin, reacts with rabbit transferrin and inhibits iron uptake and heme synthesis by rabbit reticulocytes. HTF-14 had no significant effect on iron uptake and heme synthesis when non-transferrin donors of iron were examined. Ammonium chloride (NH4Cl) increases intracellular pH and blocks the release or utilization of iron from the internalized transferrin. NH4Cl only slightly affected iron incorporation and heme synthesis from non-transferrin donors of iron. Hemin inhibited transferrin iron uptake and heme synthesis, but had a much lesser effect on iron incorporation and heme synthesis from non-transferrin donors of iron. These results allow us to conclude that transferrin-depleted reticulocytes take up iron from all of the examined non-transferrin iron donors without the involvement of the transferrin/transferrin receptor pathway.

Animals↗
PubMed1988

Properties of the transferrin associated with rat intestinal mucosa.

The transferrin that is isolated from washed intestinal mucosal cell preparations consists partly of a fraction that has properties distinguishing it from serum transferrin. The serum transferrin contaminating mucosal preparations, even when fully saturated with iron and in the presence of proteinase inhibitors, also acquires the properties of the mucosal transferrin when the mucosa is homogenised. The mucosal transferrin is modified by a single cleavage of the polypeptide chain yielding a disulphide-linked peptide of 6550 daltons linked to the parent protein by a disulphide bridge. The amino-terminal sequence of the first 11 residues of this peptide could be aligned with both the known rat and human transferrin carboxy-terminal sequences. In both cases the sequence is preceded by a phenylalanine residue (residue 622 of human transferrin). This suggested that a mucosal chymotryptic enzyme was responsible even though rat transferrin is not susceptible to alpha-chymotrypsin if fully iron-saturated. Since transferrin mRNA is not found in the intestinal mucosa it must be imported from the serum. It remains uncertain whether the modified transferrin is present naturally and plays a role in iron absorption but these findings do indicate the eventual fate of any transferrin imported into an intestinal cell.

Amino Acid Sequence↗
PubMed2006

Determination of human transferrin concentrations in mouse models of neisserial infection.

Transferrin constitutes the major protein involved in the transport of iron from the sites of absorption to the sites of storage and utilization. Despite the high affinity of transferrin for iron, most bacterial pathogens, such as the human restricted Neisseria meningitidis, have developed iron acquisition mechanisms. Several animal models of bacterial infection that include the exogenous supply of human transferrin have been implemented, and tests using transgenic mouse models are underway. Here we describe an ELISA sandwich procedure based on two monoclonal antibodies with negligible cross-reactivity to murine transferrin, to estimate human transferrin concentrations in mouse sera. The assay can detect as little as 10 ng/ml of human transferrin with coefficients of variation ranging from 1.6% to 4.4% (intra-assay) and 3.8% to 5% (inter-assay). The recovery values range from 90% to 110% in the assay working range (25-400 ng/ml). Human transferrin concentrations estimated in sera from 41 human transferrin transgenic mice ranged from 2 to 14 microg/ml. Further estimations of human transferrin levels in mouse sera of a previously described mouse model of N. meningitidis were also carried out. The intraperitoneal injection of 8 mg of human transferrin achieved a sustained value of human transferrin in mouse sera in the range of 1-2mg/ml over the first 24h, indicating that bacteria reaching the blood stream during this time would be exposed to levels of hTf found in normal human serum.

Animals↗
PubMed2003

Transferrin microheterogeneity in pregnancies with preeclampsia.

BACKGROUND: It has been reported that concentrations of serum transferrin (Tf) and its highly sialylated subfraction increase in normal pregnancy. This study investigated changes in the concentrations of serum transferrin and its subfractions in preeclampsia. METHODS: The serum concentration of transferrin was determined by a standard turbidimetric assay and microheterogeneous transferrin subgroups (low sialylated, 4-sialo and highly sialylated transferrins) were assessed by crossed immuno-isoelectric focusing. RESULTS: Compared to normal pregnancy, the concentrations of total, 4-sialo and highly sialylated transferrins decreased by 27%, 16% and 38%, respectively, in severe preeclampsia, while these values did not significantly decrease in mild preeclampsia. The concentration of low sialylated transferrin involving 2-sialo- and 3-sialo-transferrins significantly decreased both in mild and severe preeclampsia, the value in severe preeclampsia was even significantly lower than that in nonpregnant women. The serum concentrations of total and highly sialylated transferrins in preeclampsia were correlated positively with infant birth weights (r=0.587 and r=0.645, respectively). CONCLUSIONS: The serum concentrations of total and highly sialylated transferrins in severe preeclampsia decrease significantly. This might have a negative impact on intrauterine growth. Additionally, the serum low sialylated transferrin decreases more sensitively in preeclampsia, although the concentration is low even in normal pregnancy.

Birth Weight↗
PubMed1982

An alternative model for the binding and release of diferric transferrin by reticulocytes.

The biphasic binding of diferric transferrin to reticulocytes has been reevaluated with a series of kinetic and equilibrium studies. Identical binding progress profiles were observed for reticulocytes in the presence or absence of oxygen. The relative size of the rapid initial adsorption step could be increased to ca. 65% of the total binding by stripping the cells of endogenous transferrin or reduced to 0% by preloading the cells with nonradiolabeled diferric transferrin. Preloading the cells with 125I-labeled diferric transferrin and chasing with 131I-labeled diferric transferrin revealed identical rate constants for release and binding. Scatchard plots of equilibrium binding of diferric transferrin to reticulocytes showed no significant effects of anaerobiasis or 2,4-dinitrophenol on the equilibrium binding constant or the maximum number of binding sites. The potent microtubule inhibitor nocodazole had no effect on the progress curves for transferrin binding or iron uptake by reticulocytes. It was concluded that the rapid adsorption step in the binding profile represents binding to open receptors and that the slow first-order binding phase represents binding of radiolabeled transferrin to receptors already occupied by nonlabeled endogenous transferrin as this endogenous transferrin leaves the receptors. Furthermore, this first-order binding phase, unlike iron uptake, does not require the presence of active oxidative phosphorylation. These findings are consistent with a specific desorption-adsorption model for the interaction of diferric transferrin with reticulocytes.

2,4-Dinitrophenol↗