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PubMed1994

[The inhibitory effect and its mechanism of transferrin on FSH-induced differentiation of granulosa cells].

Transferrins are a class of related metal-binding transport glycoproteins for transporting iron to various organs and tissues of the body. In recent years, it has been reported that the transferrin can play an important role in the local regulation of ovarian function, apart from its iron-binding characteristic. Transferrin could attenuate FSH-induced differentiation of rat and human granulosa cells and its mechanisms were considered as follows: (1) Transferrins partially blocked the binding of FSH with its receptors on granulosa cells and reduced the formation of intracellular cAMP, and therefore inhibited the expression of FSH receptors. (2) Acting sites beyond cAMP formation also existed for the inhibitory effect of transferrin on inhibin and estradiol production. (3) The inhibitory effect of transferrin seemed not to be involved in the changes of protein kinase C activity, the calcium release and "proliferation-differentiation reversed mechanism" in granulosa cells.

Animals↗
PubMed1994

Quantitative analysis of protein synthesis inhibition by transferrin-toxin conjugates.

A mathematical model was developed which relates the time and concentration dependence of protein synthesis inhibition of an immunotoxin to the properties of the targeting agent and the conjugated toxin. The role of the targeting agent and that of the toxin in determining the cytotoxicity were separated in this model by describing protein synthesis inhibition as a function of a cellular trafficking variable, which is calculated from the trafficking parameters of the targeting agent, and a protein synthesis inhibition constant, which is a property of the translocation and enzymatic rate constants of the toxin. Transferrin cellular trafficking parameters were determined experimentally for HeLa and SK-MEL-2 cells. Protein synthesis inhibition of transferrin-gelonin and transferrin-CRM107 conjugates in both cell lines was measured as a function of time and concentration. Analysis of the data showed that the model was a good representation of the experimental results, and correctly explained cell line differences in sensitivity to transferrin-toxin conjugates. The translocation rate constant for transferrin-CRM107 was approximately 3000 times greater than that for transferrin-gelonin. The model may be useful in understanding the factors that influence immunotoxin efficacy and in designing more lethal immunotoxins.

Cell Membrane↗
PubMed1994

Interleukin-6 enhances hepatic transferrin uptake and ferritin expression in rats.

To explore a mechanism of interleukin (IL)-6-induced hypoferremia in rats, iron metabolism was investigated both in vivo and in vitro. Recombinant IL-6 was intraperitoneally administered to male Wistar rats and the serial change of parameters related to iron metabolism was examined. After administration of IL-6, plasma IL-6 concentration increased rapidly, reached its maximum in 1 hr and thereafter decreased quickly. Plasma IL-6 3 hr after IL-6 injection (50 micrograms/kg) was 3 units/ml, which is a concentration capable of inducing hepatic 125I-labeled transferrin uptake in vitro using isolated hepatocytes. Plasma iron concentration and transferrin saturation had decreased to approximately one third of the initial level within 3 hr and then recovered. Total iron binding capacity remained unchanged for 6 hr, then began to decrease. Red blood cell count and hemoglobin concentration showed no remarkable changes during this period. By ferrokinetic study with plasma that contained iron 59-labeled transferrin, the plasma iron disappearance half time, calculated from the disappearance curve, was significantly shortened from 55 min to 22 min by IL-6 treatment (p < 0.01). The ferritin concentration in the liver was increased significantly after the administration of IL-6 (p < 0.001), but transiently decreased in the spleen. The plasma ferritin showed a gradual increase during the 6-hr period after IL-6 injection. The uptake of 125I-labeled diferric transferrin by isolated hepatocytes was increased by IL-6 treatment and this increment was inhibited by addition of 100-fold excess unlabeled transferrin. On the other hand, no significant increment of 125I-labeled diferric transferrin uptake was observed in Kupffer cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1977

Effect of iron saturation of transferrin on hepatic iron uptake: an in vitro study.

Studies were performed to delineate the effect of percentage of saturation of transferrin and total iron concentration on the rate of uptake of iron by the perfused rat liver. Normal and iron-deficient rat livers were perfused with sera that contained varying concentrations of 59Fe-labeled iron and transferrin saturation. Varying the percentage of saturation of transferrin while maintaining a constant concentration of iron did not influence the hepatic uptake of iron. However, raising the concentration of iron in the perfusate while maintaining a constant saturation of transferrin did increase the uptake of iron by the liver. At similar concentrations of iron and transferrin saturation, iron-deficient livers took up greater amounts of iron than did normal livers. In our experiments, the hepatic uptake of transferrin-bound iron is determined by (1) the concentration of iron in perfusate and (2) the status of iron stores in the liver being perfused.

Animals↗
PubMed1993

Antigen presentation by B lymphoma cells. Requirements for processing of exogenous antigen internalized through transferrin receptors.

The Ag, pigeon cytochrome c, was delivered to the early endosomes in a form coupled to human ferric transferrin that entered APC through transferrin receptors. The processing of the transferrin-Ag conjugate by B lymphoma cells was compared with that of unconjugated native Ag that entered APC by a nonreceptor-mediated mechanism. Within 5 min after internalization, catabolized conjugate was detected in isolated early endosomes and did not accumulate in these organelles. Analysis of the rapid catabolism of the conjugate demonstrated that the Ag, not the transferrin, portion of the molecule was degraded by the APC, suggesting that similar proteases may mediate the processing of the conjugate and native Ag. The processing mechanisms of these molecules shared similarities. Treatment of APC with chloroquine or paraformaldehyde interfered with the stimulation of Ag-specific CD4+ T cells by both transferrin-Ag conjugate and native Ag. However, the T cell responses to the conjugate and native Ag were different in two important respects. First, T cell activation by the conjugate began at an earlier time point and occurred at a faster rate than T cell stimulation by the same concentration of native Ag during a 3-h time course. Second, the T cell response to the conjugate, but not to native Ag, was diminished by treating APC with cycloheximide, a reversible protein synthesis inhibitor. This partial inhibition of the conjugate response by cycloheximide could not be attributed to significant effects on transferrin receptor expression, or on internalization, recycling, or degradation of the conjugate. The differential cycloheximide-sensitivity of the T cell responses indicates that the processing pathways of the two molecules are different. Our findings suggest that the early endosomes may function as an Ag-processing compartment, and that more than one pathway may lead to productive processing in B lymphoma cells.

Antigen Presentation↗
PubMed1993

A region of the C-terminal portion of the human transferrin receptor contains an asparagine-linked glycosylation site critical for receptor structure and function.

The transferrin receptor is a cell surface protein and is responsible for the uptake of iron into many eukaryotic cells. In its mature form, the receptor possesses three asparagine-linked oligosaccharides. The effect of asparagine-linked glycosylation on the processing and cell surface localization of the human transferrin receptor is examined here by site-directed mutagenesis. Each of the extracellular consensus sequences (Asn-X-Ser/Thr) for asparagine-linked glycosylation was mutated individually and in all possible combinations. The constructs were transfected stably into NIH-3T3 cells and a Chinese hamster ovary cell line lacking endogenous transferrin receptors. Of the seven possible combinations of glycosylation sites, single mutations eliminating glycosylation at either Asn251 or Asn317 do not affect the processing and surface localization of the receptor. Eliminating both of these sites together has a small effect on the behavior of the receptor. However, mutation of the C-terminal glycosylation site (Asn727) has the most profound negative effect on the appearance of the receptor at the cell surface. The mutants lacking glycosylation at Asn727 appear to be retained in the endoplasmic reticulum as an increased association with binding immunoglobulin protein (BiP) is observed. Addition of a new glycosylation site in the C-terminal region of the unglycosylated mutated transferrin receptor restores the cell surface localization and the transferrin binding of the transferrin receptor, indicating that glycosylation in this region is critical for the correct transport of this receptor to the cell surface.

3T3 Cells↗
PubMedDate not supplied

[Carbohydrate-deficient transferrin and liver diseases. Study of 94 patients].

OBJECTIVES AND METHODS: Carbohydrate-deficient transferrin has been proposed as a marker of alcohol consumption. The aim of this study was to evaluate the accuracy of the carbohydrate-deficient transferrin serum level, measured by ion exchange chromatography followed by radioimmunoassay (Kit CDTect), for the diagnosis of excessive alcohol intake in patients with liver diseases. Ninety-four patients (68 men, 26 women, age 21-71 years), 42 with alcoholic liver diseases and 52 with non-alcoholic liver diseases, were studied. Twenty-six patients consumed > or = 40 g alcohol per day (mean alcohol intake: 84 +/- 52 g per day) and were considered to be excessive drinkers. RESULTS: The sensitivity of carbohydrate-deficient transferrin for the diagnosis of excessive alcohol intake was 35%, and the specificity was 91%. By pairing carbohydrate-deficient transferrin with other markers of alcohol consumption, the sensitivity of the association of carbohydrate-deficient transferrin and gammaglutamyl transpeptidase was 96%, and the specificity was 59%. CONCLUSION: In patients with liver diseases, carbohydrate-deficient transferrin is a specific marker of excessive alcohol intake but a lack of sensitivity may limit its use.

Adult↗
PubMed1996

Structure of medaka transferrin gene and its 5'-flanking region.

Transferrin is a monomeric iron-binding glycoprotein. To investigate the structure of the transferrin gene in teleosts, we prepared a genomic DNA library from the medaka (Oryzias latipes). The medaka transferrin gene was isolated, and its nucleotide sequence was determined. The full length of this gene is approximately 8.5 kb, and it is organized into 17 exons separated by 16 introns. The exons are similar in size to those in the genes for human transferrin, chicken ovotransferrin, and mouse and bovine lactoferrin. However, the introns are smaller than those previously reported in the transferrin family of genes. The 5'-flanking region of the medaka transferrin gene contains an estrogen-responsive element, glucocorticoid-responsive elements, an iron-responsive element, metal-responsive elements, and Sp1 binding sites. The transcription start point is located 35 bp upstream of the start codon.

Amino Acid Sequence↗
PubMed1996

Transferrin and insulin enhance human colon tumor cell growth by differentiation class specific mechanisms.

Human colon tumor cell lines that were adapted to grow in chemically defined medium were tested for their growth sensitivity to exogenous transferrin, insulin, and epidermal growth factor (EGF). Less differentiated cell lines, C and HCT116, were able to grow in the presence of a single peptide supplement, to respond synergistically to transferrin and insulin in combination, and to be insensitive to supplementation with exogenous EGF. The more differentiated cell lines, CBS and GEO, were found to respond to exogenous EGF in a concentration-dependent manner, to require at least two peptide factor supplements to support growth, and to respond synergistically when EGF was added to chemically defined medium that already contained transferrin and insulin. To investigate whether changes in the number or the affinity-classes of the EGF-receptor might be involved in any of these growth responses, changes in EGF-receptor number and dissociation constant were determined as a function of cell growth condition. The poorly differentiated HCT cell line HCT116 was found to undergo 28 to 64% increases in [125I]EGF-binding when its medium was supplemented with transferrin, insulin, or transferrin plus insulin. The more differentiated CBS cell line responded to all peptide supplements with decreases in [125I]EGF-binding ranging from 12 to 73%. These findings indicate that the actions of transferrin and insulin are fundamental to the growth regulatory mechanisms of these two differentiation classes of human colon tumor cell lines, but that their mechanisms are different.

Adenocarcinoma↗
PubMed1996

[Connection between the level of transferrin in blood plasma and the level of malondialdehyde in mouse liver].

To study possible correlation between plasma transferrin content and level of 2-thiobarbituric acid-reactive substances (malonic dialdehyde (MDA)) in the liver of mice, these parameters were assayed during brombenzol-induced lipid peroxidation and when this process was inhibited by zinc-metallothionein (zinc-MT). In 24 h after brombenzol injection (0.5-2 g/kg intraperitoneally), mice had decreased blood transferrin concentration and increased MDA level in the liver. On the contrary, in 24 h after the zinc-MT injection (1-4 mg/kg intraperitoneally), blood transferrin concentration was 2-3-fold increased and liver MDA content was 2-3-fold decreased. The effects of zinc-MT were observed even in brombenzol-injected animals. Zinc-MT injection increased total transferrin content in the blood and decreased glycosylation of this glycoprotein. Changes in blood transferrin content negatively correlates (r = -0.75) with changes in liver MDA. The data confirm that plasma transferrin can participate in regulation of tissue lipid peroxidation.

Animals↗
PubMed1998

Validation by isoelectric focusing of the anion-exchange isotransferrin fractionation step involved in determination of carbohydrate-deficient transferrin by the CDTect assay.

Serum concentration of carbohydrate-deficient transferrin (CDT) is used for laboratory diagnosis of chronic alcohol abuse. Using isoelectric focusing for validation of the initial isotransferrin fractionation step involved in the determination of CDT by the CDTect assay, we found a complete in vitro iron saturation of transferrin and sufficient stability of the transferrin iron load during column passage; effective separation of non-CDT-isotransferrins and CDT-isotransferrins at the microcolumns; partial coelution of trisialo-Fe2-transferrin, which did not significantly affect CDT measurement; partial retention of CDT-isotransferrins, especially disialo-Fe2-transferrin, which may cause falsely negative results for CDT at the upper reference limits; good precision of the isotransferrin fractionation step; and no significant effects of low concentrations of serum protein and transferrin. We strongly urge standardization of CDT analysis and suggest isoelectric focusing for validation of CDT analysis methods and verification of odd results.

Alcoholism↗
PubMed1998

Molecular cloning and evolution of transferrin cDNAs in salmonids.

Transferrin complementary DNAs were cloned from the livers of seven species in three genera of salmonids (kokanee salmon Oncorhynchus nerka, amago salmon Oncorhynchus masou ishikawa, masu salmon Oncorhynchus masou masou, Japanese char Salvelinus pluvius, brook trout Salvelinus fontinalis, lake trout Salvelinus namaycush, and brown trout Salmo trutta) subsequent to polymerase chain reaction amplification with primers derived from conserved regions of transferrin cDNA sequences. The transferrin cDNAs of the seven species of salmonids had sizes of 2.2 to 2.4 kb and encoded an open reading frame consisting of 691 amino acids with a putative signal peptide of 18 amino acids. The alignment of salmonid transferrin cDNAs showed a duplicated structure and conserved anion-binding residues, iron-binding residues, and cysteine residues for disulfide bridges. The deduced amino acid sequences of the seven salmonid transferrin cDNAs share 85% to 99% homology. A phylogenetic tree of amino acid sequences of transferrin cDNAs from salmonids showed that the relationship among the three genera of salmonids (Oncorhynchus, Salvelinus, and Salmo) is well correlated with that derived from classic morphologic and genetic analyses.

Amino Acid Sequence↗
PubMed1997

Energy-dependent changes in the gonococcal transferrin receptor.

The pathogenic Neisseria spp. are capable of iron utilization from host iron-binding proteins including transferrin and lactoferrin. Transferrin iron utilization is an energy-dependent, receptor-mediated event in which two identified transferrin-binding proteins participate. One of these proteins, TbpA, is homologous to the TonB-dependent family of outer membrane receptors that are required for high-affinity uptake of vitamin B12 and ferric siderophores. The 'TonB box' is a conserved domain near the amino-terminus of these proteins that has been implicated in interaction with TonB. Interaction between a periplasmic domain of TonB and the TonB box allows energy transduction to occur from the cytoplasmic membrane to the energy-dependent receptor in the outer membrane. We created a TonB box mutant of gonococcal TbpA and demonstrated that its binding and protease accessibility characteristics were indistinguishable from those of gonococcal Ton system mutants. The protease exposure of the second transferrin-binding protein, TbpB, was affected by the energization of TbpA, consistent with an interaction between these proteins. TbpB expressed by the de-energized mutants was readily accessible to protease, similar to TbpB expressed in the absence of TbpA. The de-energized mutants exhibited a marked decrease in transferrin diffusion rate, suggesting that receptor energization was necessary for ligand release. We propose a model to explain the observed Ton-dependent changes in the binding parameters and exposures of TbpA and TbpB.

Bacterial Outer Membrane Proteins↗
PubMed1993

Rate of 59Fe uptake into brain and cerebrospinal fluid and the influence thereon of antibodies against the transferrin receptor.

Uptake of 59Fe from blood into brains of anaesthetized rats and mice has been studied by intravenous infusion of [59Fe]ferrous ascorbate or of 59Fe-transferrin, the results not being significantly different. Uptakes in the rat were linear with time, but increased at longer times in the mouse. Transfer constants, K(in) (in ml/g/h x 10(3)), for cerebral hemispheres were 5.2 in the adult rat and 5.6 in the mouse. These K(in) values corresponded to 59Fe influxes of 145 and 322 pmol/g/h, respectively. 59Fe uptake into the mouse brain occurred in the following order: cerebellum > brainstem > frontal cerebral cortex > parietal cortex > occipital cortex > hippocampus > caudate nucleus. In genetically hypotransferrinaemic mice, 59Fe uptake into brain was 80-95 times greater than in To strain mice. Pretreatment of young rats and mice with monoclonal antibodies to transferrin receptors, i.e., the anti-rat immunoglobulin G OX 26 and the anti-mouse immunoglobulin M RI7 208, inhibited 59Fe uptake into spleen by 94% and 98%, respectively, indicating saturation of receptors. The antibodies reduced 59Fe uptake into rat brain by 35-60% and that into mouse brain by 65-85%. Although a major portion of iron transport across the blood-brain barrier is normally transferrin-mediated, non-transferrin-bound iron readily crosses it at low serum transferrin levels.

Animals↗
PubMed1992

Common antigenic domains in transferrin-binding protein 2 of Neisseria meningitidis, Neisseria gonorrhoeae, and Haemophilus influenzae type b.

There is now considerable evidence to show that in the Neisseria and Haemophilus species, membrane receptors specific for either transferrin or lactoferrin are involved in the acquisition of iron from these glycoproteins. In Neisseria meningitidis, the transferrin receptor appears to consist of two proteins, one of which (TBP 1) has an M(r) of 95,000 and the other of which (TBP 2) has an M(r) ranging from 68,000 to 85,000, depending on the strain; TBP 2 binds transferrin after sodium dodecyl sulfate-polyacrylamide gel electrophoresis and electroblotting, but TBP 1 does not do so. The relative contributions of these two proteins to the binding reaction observed with intact cells and to iron uptake are presently unknown. However, they are being considered as potential components of a group B meningococcal vaccine. Analogous higher- and lower-molecular-weight proteins associated with transferrin binding have been found in N. gonorrhoeae and Haemophilus influenzae. Previous work with polyclonal antibodies raised in mice with whole cells of iron-restricted N. meningitidis showed that the meningococcal TBP 2 exhibits considerable antigenic heterogeneity. Here, we report that antiserum against purified TBP 2 from one strain of N. meningitidis cross-reacts on immunoblotting with the TBP 2 of all meningococcal isolates examined, as well as with the TBP 2 of N. gonorrhoeae. This antiserum also cross-reacted with the TBP 2 of several strains of H. influenzae type b, thus showing the presence of common antigenic domains among these functionally equivalent proteins in different pathogens; no cross-reaction was detected with a purified sample of the human transferrin receptor.

Animals↗
PubMed1999

Construction and characterization of Moraxella catarrhalis mutants defective in expression of transferrin receptors.

We have previously reported the construction of an isogenic mutant defective in expression of OmpB1, the TbpB homologue, in Moraxella catarrhalis 7169. In this report, we have extended these studies by constructing and characterizing two new isogenic mutants in this clinical isolate. One mutant is defective in expression of TbpA, and the other mutant is defective in expression of both TbpA and TbpB. These isogenic mutants were confirmed by using PCR analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and sequencing. In vitro growth studies, comparing all three mutants, demonstrated that the tbpA mutant and the tbpAB mutant were severely limited in their ability to grow with human holotransferrin as the sole source of iron. In contrast, the ompB1 (tbpB) mutant was capable of utilizing iron from human transferrin, although not to the extent of the parental strain. While affinity chromatography with human holotransferrin showed that each Tbp was capable of binding independently to transferrin, solid-phase transferrin binding studies using whole cells demonstrated that the tbpA mutant exhibited binding characteristics similar to those seen with the wild-type bacteria. However, the ompB1 (tbpB) mutant exhibited a diminished capacity for binding transferrin, and no binding was detected with the double mutant. These data suggest that the M. catarrhalis TbpA is necessary for the acquisition of iron from transferrin. In contrast, TbpB is not essential but may serve as a facilitory protein that functions to optimize this process. Together these mutants are essential to provide a more thorough understanding of iron acquisition mechanisms utilized by M. catarrhalis.

Bacterial Outer Membrane Proteins↗
PubMed2004

Determination of surface-exposed, functional domains of gonococcal transferrin-binding protein A.

The gonococcal transferrin receptor is composed of two distinct proteins, TbpA and TbpB. TbpA is a member of the TonB-dependent family of integral outer membrane transporters, while TbpB is lipid modified and thought to be peripherally surface exposed. We previously proposed a hypothetical topology model for gonococcal TbpA that was based upon computer predictions and similarity with other TonB-dependent transporters for which crystal structures have been determined. In the present study, the hemagglutinin epitope was inserted into TbpA to probe the surface topology of this protein and secondarily to test the functional impacts of site-specific mutagenesis. Twelve epitope insertion mutants were constructed, five of which allowed us to confirm the surface exposure of loops 2, 3, 5, 7, and 10. In contrast to the predictions set forth by the hypothetical model, insertion into the plug region resulted in an epitope that was surface accessible, while epitope insertions into two putative loops (9 and 11) were not surface accessible. Insertions into putative loop 3 and beta strand 9 abolished transferrin binding and utilization, and the plug insertion mutant exhibited decreased transferrin-binding affinity concomitant with an inability to utilize it. Insertion into putative beta strand 16 generated a mutant that was able to bind transferrin normally but that was unable to mediate utilization. Mutants with insertions into putative loops 2, 9, and 11 maintained wild-type binding affinity but could utilize only transferrin in the presence of TbpB. This is the first demonstration of the ability of TbpB to compensate for a mutation in TbpA.

Amino Acid Sequence↗
PubMed1990

Characterization of transferrin receptors on plasma membranes of lactating rat mammary tissue.

Little is known about the transport of iron into the mammary secretory cell and the process of milk iron secretion. The concentration of iron in milk is remarkably unaffected by maternal iron status, suggesting that the uptake of iron into the mammary gland is regulated. It is known that iron enters other cells via transferrin receptor-mediated endocytosis. This study was designed to isolate and characterize the mammary gland transferrin receptor in lactating rat mammary tissue using immunochemical techniques. The existence of functional mammary gland transferrin receptors in lactating rodents was demonstrated using radiolabel-binding techniques. Isolation of mammary transferrin receptors by affinity chromatography was confirmed using immunoelectrophoresis and slot blot analysis. The intact transferrin receptor was found to have a molecular weight of 176 kd as determined by Western blotting followed by scanning densitometry. Reduction of the receptor with beta-mercaptoethanol gave a molecular weight of 98 kd. An additional immunoreactive band of 135 kd was observed. The presence of transferrin receptors in normal lactating rat mammary tissue is likely to explain iron transport into mammary tissue for both cellular metabolism and milk iron secretion.

Journal Article↗