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PubMed2002

Transferrin up-regulates chemokine synthesis by human proximal tubular epithelial cells: implication on mechanism of tubuloglomerular communication in glomerulopathic proteinura.

BACKGROUND: The pathogenesis of glomerulosclerosis and tubulointerstitial fibrosis in proteinuric renal disease is obscure. We recently showed that transferrin, a key proteinuric component, mediates proximal tubular epithelial cell (PTEC) C3 synthesis. To further examine whether proteinuric tubular injury may induce glomerular inflammation and to characterize the role of transferrin in activating PTEC, glomerular mesangial cells (MC) were exposed to transferrin-activated PTEC culture supernatant and their proliferative and profibrotic responses analyzed. METHODS: Human PTEC and MC were obtained by primary culture. Confluent, transferrin-stimulated PTEC were grown in serum-free medium to produce a "conditioned" medium that was incubated with quiescent MC. The proliferative response of MC was then assessed by thymidine uptake, and the expression of fibrogenic factors measured by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). The chemokine profile in PTEC after transferrin treatment was examined by RT-PCR and ELISA. RESULTS: "Conditioned" supernatant from PTEC, which contained the highest amounts of platelet-derived growth factor (PDGF), stimulated MC proliferation compared with serum-free (P = 0.03) or transferrin-containing (P = 0.009) control media. This proliferative response was partially abrogated by treating MC with anti-PDGF. MC expression of PDGF, but not transforming growth factor-beta or intercellular cell adhesion molecule-1, was up-regulated by conditioned PTEC medium. Transferrin up-regulated monocyte chemoattractant peptide-1, interleukin-8, and macrophage migration inhibitory factor expression in a time- and dose-dependent fashion, but had no effect on RANTES expression by PTEC. CONCLUSIONS: These results provide experimental evidence suggesting that there is a tubuloglomerular "cross-talk" mechanism in the proteinuric state. PTEC-secreted PDGF, which further induces mesangial PDGF, could partially account for the mesangial proliferation frequently observed in proteinuric renal disease. Transferrin is one of the culprit nephrotic proteins leading to tubular overexpression of various proinflammatory chemokines, which may explain the interstitial changes observed in proteinuric states.

Antibodies↗
PubMed1996

Molecular regulation of transferrin receptor and ferritin expression in the rat gastrointestinal tract.

BACKGROUND & AIMS: The role of the transferrin receptor and ferritin i n the regulation of intestinal dietary iron uptake and excretion is unknown. This study aimed to determine the regulation of transferrin receptor and ferritin messenger RNA (mRNA) in the rat gastrointestinal tract in response to dietary iron changes. METHODS: In situ hybridization studies for transferrin receptor and L-ferritin mRNAs were performed using tissues from normal-iron-deficient, and iron-loaded rats. RESULTS: L-ferritin mRNA was localized to small intestinal crypt and villus epithelial cells and colonic crypt and surface epithelial cells with mRNA levels up-regulated in iron-loaded rats. Transferrin receptor mRNA was detected in crypt epithelial cells of the small and large intestine in iron-deficient and normal rats. In contrast, in iron-loaded rats, transferrin receptor mRNA was also detected in the superficial epithelial cells of the small intestine and colon, which contained increased stores of iron. Transferrin receptor mRNA levels were increased in the colon. CONCLUSIONS: In the iron-deficient and normal rat intestine, transferrin receptor mRNA was expressed only by proliferating crypt epithelial cells. In iron-loaded rats, however, surface enterocytes of the intestine expressed both transferrin receptor mRNA and increased ferritin mRNA levels.

Animals↗
PubMed1981

Radioimmunochemical measurement of the transferrin receptor in human trophoblast and reticulocyte membranes with a specific anti-receptor antibody.

A radioimmunoassay was developed to directly assay the presence of transferrin receptors in human tissues. Antisera developed in a goat against purified human placental transferrin binding protein was purified by fractional sodium sulfate precipitation and adsorption against Sepharose-bound transferrin to remove trace anti-transferrin activity. The antisera immunoprecipitates a Mr 94,000 peptide on 125I-iodinated syncytial trophoblast membranes from placentae. This polypeptide has been identified previously as the transferrin binding protein of the placenta [Wada, H. G., Hass, P. E. & Sussman, H. H. (1979) J. Biol. Chem. 254, 12629-12635]. A standard curve using purified 125I-iodinated placental transferrin receptor and various amounts of the purified noniodinated receptor is sensitive from 5 to 900 ng. A reticulocyte-enriched membrane ghost preparation (5% reticulocyte) gives a value of 9.5 micrograms of receptor per mg of protein. Normal erythrocyte membrane ghosts show binding (0.57 micrograms of receptor per mg of protein) proportional to the amount of reticulocytes normally present in blood (0.5-1.0%). In other tissues in which the transferrin receptor binding has been reported, purified syncytial trophoblastic membranes are found to have 34.5 micrograms of receptor per mg of protein, and BeWo cells, a choriocarcinoma cell line, are found to have 15.7 micrograms of receptor per mg of protein. In contrast, normal breast tissue, which has no demonstrated transferrin binding, contains only 0.18 micrograms of receptor per mg of protein by this method.

Breast↗
PubMed1985

Transferrin gene expression visualized in oligodendrocytes of the rat brain by using in situ hybridization and immunohistochemistry.

The presence and production of transferrin in the adult rat brain have been investigated using both immunohistochemistry and in situ hybridization in tissue sections. Indirect immunofluorescence with four distinct antisera against rat and human transferrin and one monoclonal antibody against human transferrin demonstrated labeling of the cytoplasm of oligodendrocytes (a category of glial cells) in most parts of the brain, especially in the white matter. In situ hybridization using rat transferrin 32P-labeled cDNA as a probe revealed the presence of transferrin mRNA in glial cells whose appearance, distribution, and organization exactly matched those of the cells decorated with the transferrin antibodies. These results provide evidence that the transferrin gene is expressed in the central nervous system and that transferrin is synthesized by and stored within oligodendrocytes in the adult rat brain. These data suggest that this molecule could have a specific function in nervous system activity.

Animals↗
PubMed1987

Tissue distribution and clearance kinetics of non-transferrin-bound iron in the hypotransferrinemic mouse: a rodent model for hemochromatosis.

Genetically hypotransferrinemic mice accumulate iron in the liver and pancreas. A similar pattern of tissue iron accumulation occurs in humans with hereditary hemochromatosis. In both disorders, there is a decreased plasma concentration of apotransferrin. To test the hypothesis that nontransferrin-bound iron exists and is cleared by the parenchymal tissues, the tissue distribution of 59Fe was studied in animals lacking apotransferrin. Two groups of animals were used: normal rats and mice whose transferrin had been saturated by an intravenous injection of nonradiolabeled iron, and mice with congenital hypotransferrinemia. In control animals, injected 59Fe was found primarily in the bone marrow and spleen. In the transferrin iron-saturated animals, injected 59Fe accumulated in the liver and pancreas. Gastrointestinally absorbed iron in hypotransferrinemic or transferrin iron-saturated mice was deposited in the liver. This indicates that newly absorbed iron is released from mucosal cells not bound to transferrin. Clearance studies demonstrated that transferrin-bound 59Fe was removed from the circulation of rats with a half-time of 50 min. In transferrin iron-saturated animals, injected 59Fe was removed with a half-time of less than 30 s. Analysis of the distribution of 59Fe in serum samples by polyacrylamide gel electrophoresis demonstrated the presence of 59Fe not bound to transferrin. These results demonstrate the existence of and an uptake system for non-transferrin-bound iron. These observations support the hypothesis that parenchymal iron overload is a consequence of reduced concentrations of apotransferrin.

Animals↗
PubMed1988

Two genetic loci participate in the regulation by iron of the gene for the human transferrin receptor.

Iron regulation of the human transferrin receptor gene was examined in murine cells transformed with chimeric constructs containing the human transferrin receptor gene's promoter and either the structural gene for bacterial chloramphenicol acetyltransferase or the human transferrin receptor cDNA. The activity of the transferrin receptor gene's promoter with the heterologous indicator gene was found to be approximately equal to 3-fold higher in cells treated with the iron chelator desferrioxamine than in cells treated with the iron source, hemin. A higher degree of iron regulation was seen in the expression of the human transferrin receptor cDNA driven by its own promoter. The receptor cDNA under the control of the simian virus 40 early promoter was also iron-regulated. Several human transferrin receptor transcripts differing in their 3' end were produced in the murine cells regardless of the promoter used, with the shorter transcripts being relatively unregulated by iron. Deletion of cDNA corresponding to most of the 3' untranslated portion of the mRNA for the receptor ablated the iron regulation. We conclude that at least two genetic elements exist for the regulation of the transferrin receptor gene by iron. One has its locus in the DNA upstream of the transferrin receptor gene's transcription start site, and the other is dependent upon the integrity of the sequences in the 3' end of the gene.

Acetyltransferases↗
PubMed1993

Transferrin in a cockroach: molecular cloning, characterization, and suppression by juvenile hormone.

In a study of juvenile hormone-regulated gene expression, we isolated an anonymous cDNA representing a message that was strongly suppressed by juvenile hormone in the fat body of the cockroach Blaberus discoidalis. The protein deduced from the cDNA sequence showed compelling resemblance in sequence to the transferrins, a superfamily of internally duplicated, 80-kDa iron-binding/transport proteins characterized from several vertebrates and, to date, one insect (the tobacco hornworm, Manduca sexta). We isolated a 78-kDa protein from cockroach hemolymph, verified its congruence with the cloned cDNA, and found that it did bind iron. The cockroach protein is a member of the transferrin superfamily based on several features, including 32-46% amino acid positional identity with transferrins whose sequences are known, internal homology, positioning of cysteine residues, and iron binding. Whereas the previously characterized insect transferrin binds one atom of iron per protein molecule, B. discoidalis transferrin binds two iron atoms as do the vertebrate transferrins. The diferric property of cockroach transferrin is consistent with presence of two sets of residues positioned appropriately for iron binding. Juvenile hormone suppressed transferrin mRNA levels drastically in the adult female cockroach.

Adipose Tissue↗
PubMed1999

Identification of a hypoxia response element in the transferrin receptor gene.

Expression of the transferrin receptor, which mediates iron uptake from transferrin, is negatively regulated post-transcriptionally by intracellular iron through iron-responsive elements in the 3'-untranslated region of the transferrin receptor mRNA. Transcriptional mechanisms are also involved in receptor expression, but these are poorly understood. In this study we have characterized the transferrin receptor promoter region and identified a functional hypoxia response element that contains a binding site for hypoxia-inducible factor-1 (HIF-1). Exposure of K562 and HeLa cells to hypoxia for 16 h resulted in a 2- to 3-fold increase in transferrin receptor mRNA expression. A motif with multipartite organization similar to the hypoxia response element of a number of hypoxia-inducible genes such as erythropoietin was identified within a 100-base pair sequence upstream of the transcriptional start site. Mutation of a site similar to the consensus HIF-binding site (HBS) in this motif attenuated the hypoxic response by 80%. Transient co-expression of the two HIF-1 subunits (HIF-1alpha and HIF-1beta) enhanced the wild type transferrin receptor promoter activity, but that which contained a mutated HBS yielded no such response. Electrophoretic mobility shift assays revealed that HIF-1 was stimulated and bound to the transferrin receptor HBS upon hypoxic challenge. Our results indicate that the transferrin receptor is a target gene for HIF-1.

Base Sequence↗
PubMed1988

Intracellular colocalization of variant surface glycoprotein and transferrin-gold in Trypanosoma brucei.

Endocytosis and intracellular transport has been studied in the bloodstream forms of Trypanosoma brucei by light and electron microscopy, using colloidal gold coupled to bovine transferrin (transferrin-gold). The endocytosed transferrin-gold, visualized by silver intensification for light microscopy, was present in vesicular structures between the cell nucleus and flagellar pocket of the organism. At the ultrastructural level, transferrin-gold was present after a 10-min incubation in the flagellar pocket, coated vesicles, cisternal networks, and lysosomelike structures. Endocytosis and intracellular processing of T. brucei variable surface glycoprotein (VSG) was studied using two preparations of affinity-purified rabbit IgG directed against different parts of the VSG. One preparation of IgG was directed against the cross-reacting determinant (CRD): a complex glycolipid side chain covalently linked to the COOH-terminus of the VSG molecule. The other was directed against determinants on the rest of the VSG molecule. When the two IgG preparations were used on thawed, thin cryosections of trypanosomes that had been incubated in transferrin-gold before fixation, the organelles involved with transferrin-gold endocytosis labeled with both antibodies, as well as many vesicular, tubular, and vacuolar structures that did not contain endocytosed transferrin-gold. Both antibodies also labeled the cell surface. In double-labeling experiments both antibodies were closely associated except that IgG directed against the VSG molecule labeled all the cisternae of the Golgi apparatus, whereas anti-CRD IgG was shown to label only half of the Golgi apparatus. Evidence for sorting of VSG molecules from endocytosed transferrin-gold was found. Double-labeling experiments also showed some tubular profiles which labeled on one side with anti-CRD IgG and on the other side with anti-VSG IgG, suggesting a possible segregation of parts of the VSG molecule.

Animals↗
PubMed1991

Monoclonal antibodies to the amino- and carboxyl-terminal domains of human transferrin.

Seven high affinity antibodies to human serum transferrin which recognize at least four different epitopes are described. Apparent dissociation constants (Kd's) have been determined for the binding of the antibodies to human transferrin in the presence and absence of iron. Small differences in reactivity were found. Five of the antibodies bind to the isolated amino-terminal half-molecule of human transferrin. Two of the antibodies appear to be to the C-terminal lobe since they bind to holo-transferrin but do not recognize the N-terminal half-molecule. Immunoblotting shows that six of the antibodies recognize both reduced and nonreduced transferrin. In addition, all of the antibodies bind with sufficiently high avidity to transferrin to make them useful as probes in studies in which binding of transferrin to the specific transferrin receptor is examined.

Animals↗
PubMed1988

Effect of extended lactation and diet on transferrin concentrations in rat milk.

Milk transferrin in the rat is immunochemically identical to serum transferrin. Its concentration in milk during normal lactation (10 pups for 21 d) varies biphasically, decreasing from a value of 1.5 mg/ml in colostrum to barely detectable values at d 4 and 8 of lactation, and thereafter increasing to reach values of 4 mg/ml at d 21. The effect of extended lactation on transferrin in milk was investigated in two experiments in which litters were replaced by 4-d-old litters at d 8 and 12 of lactation or at d 20 of lactation. Transferrin concentrations in milk in both experiments increased in a similar manner to reach values of 10 mg/ml at d 28 through d 36 of lactation. Serum transferrin and serum insulin and prolactin concentrations were not significantly altered in these experiments. Premature exposure of dams to older pups did not affect the pattern of milk transferrin concentrations. Milk transferrin concentrations were, however, modulated by altering the milk demand (changing litter sizes) and by restricting either the total food intake or the protein content of the diet. These restrictions led to lower transferrin concentrations.

Animals↗
PubMed2004

Positive selection on multiple antique allelic lineages of transferrin in the polyploid Carassius auratus.

Transferrin polymorphism has been studied in the polyploid Carassius auratus by cloning and sequence analysis of cDNAs from its three subspecies C. auratus gibelio, C. auratus auratus, and C. auratus cuvieri. DNA polymorphism of extremely high extent was shown for the transferrin gene by the 248 segregation sites among coding region sequences of its alleles. The deduced amino acid sequences of the transferrin alleles showed variable theoretical physicochemical parameters, which might constitute molecular basis for their electrophoretic heterogeneity. Positive selection was inferred by the replacement/synonymous ratios larger than 1 in partial allelic lineages which was subsequently confirmed by likelihood simulation under neutral or selection models. Furthermore, the correspondent sites to these selected codons were collectively located at two planes in the crystallographic structure of rabbit transferrin, which suggested that the rapid evolution of C. auratus transferrin might correlate to its adaptation to variable environmental elements such as oxygen pressure. The minimal 26 recombination events were detected among coding sequences of C. auratus transferrin, with partial mosaic sequences and breakpoints identified by identity scanning and information site analyses. Phylogenetic analyses revealed multiple antique allelic lineages of transferrin, which was estimated to diverge fifteen to twenty MYA. All these features strongly suggested the role of balancing selection in long persistence of high transferrin polymorphism in C. auratus. Furthermore, owing to its particular evolutionary backgrounds, the silver crucian carp might possess a distinctive balancing selection mechanism.

Alleles↗
PubMed1992

Post-transcriptional regulation of transferrin receptor mRNA by IFN gamma.

IFN gamma inhibits the rise in transferrin receptor mRNA level which is normally observed when stationary WISH cells are stimulated to proliferate. This effect is not attributable to a change in the transcription rate of the transferrin receptor gene or in the cytoplasmic stability of the mRNA. The IFN gamma-induced reduction of the transferrin receptor mRNA content is already present at the nuclear level to an extent comparable to that observed in whole cells. Thus, IFN gamma does not impair the passage of this mRNA from the nuclear to the cytoplasmic compartment but probably interferes with a nuclear post-transcriptional event during the processing of the immature transferrin receptor mRNA. Two different levels of regulation of transferrin receptor mRNA have been previously reported. Iron modulates the cytoplasmic stability of this mRNA through the binding of a specific cytoplasmic factor, whereas cell growth variation influences the transcription of this gene. Our results suggest the existence of another mechanism of regulation for transferrin receptor gene expression not so far considered. Furthermore, the distinction between the mechanism of regulation exerted by IFN gamma and that exerted by cell proliferation on transferrin receptor gene expression suggests that, in WISH cells, the IFN-induced transferrin receptor decay is not a consequence of cell growth arrest but rather one of the causes of the antiproliferative effect of IFN through iron deprivation.

Blotting, Northern↗
PubMed1988

Stimulation of rat placental cell DNA synthesis by transferrin.

The purpose of the present investigation was to evaluate the in vitro requirements for rat placental cell DNA synthesis. A cell line established from the labyrinth region of midgestation rat chorioallantoic placentas was used to examine the actions of various agents. Transferrin was found to stimulate rat placental cell DNA synthesis and cell proliferation. The effects of transferrin on rat placental cell growth paralleled those observed with fetal bovine serum. Rat placental cells were responsive to both rat and human transferrin. Iron-saturated (holo-) transferrin was a more potent stimulator of rat placental cell DNA synthesis than was iron-free (apo-) transferrin. Addition of insulin, epidermal growth factor, or insulin-like growth factor-II to serum-free medium supplemented with rat transferrin did not significantly enhance rat placental cell DNA synthesis beyond that observed with only transferrin. The results demonstrate that a population of cells exists within the rat chorioallantoic placenta that are highly responsive to transferrin.

Animals↗
PubMed2005

Rapid alterations in transferrin sialylation during sepsis.

The inflammatory process is associated with alterations in iron metabolism. Transferrin, an acute-phase N-glycosylated glycoprotein, plays an important role in iron transport. Human serum transferrin contains two biantennary glycans, each consisting of 0 to 4 molecules of sialic acid (SA); its SA content is heterogeneous with high concentration of tetrasialotransferrin (4SA) and low amounts of disialo-, trisialo-, penta-, and hexasialotransferrin. The hepatic uptake of iron is greater for desialylated transferrin isoforms (disialotransferrin) than for the other forms. We hypothesized that serum levels of carbohydrate-deficient transferrin (CDT, disialotransferrin) may increase rapidly in septic patients. Blood samples were obtained from critically ill patients with (n = 15) and without (n = 14) documented sepsis and compared with healthy volunteers. The different forms of transferrin were studied by capillary zone electrophoresis; SA concentrations were measured by enzymatic colorimetric assay. There was a significant increase in the proportion of CDT in septic compared with nonseptic patients and volunteers (18.3% [1.3-30.5] vs. 0.7% [0.5-0.9]; P < 0.01 and 0.9% [0.5-1.1]; P < 0.05). Conversely, tri- and tetrasialotransferrin levels were lower in septic patients. Total and free SA concentrations were significantly higher in septic patients than in healthy volunteers. In a sheep model of septic shock secondary to peritonitis, serum free SA was already increased after 15 h. Sepsis is associated with decreased SA content on circulating transferrin and with an increase in blood free SA concentrations. In view of these rapid modifications and the long half-life of transferrin, the most likely explanation is degradation of transferrin by neuraminidase. Further studies including measurement of blood neuraminidase concentration and activity are needed to understand the process and exact role of SA decrease in septic patients.

Acute Disease↗
PubMed1981

Specific enhancement of mouse CFU-E by mouse transferrin.

Pure human and mouse transferrins were prepared by a chromatographic procedure and their effect on the growth of early (BFU-E) and late (CFU-E) erythropoietic precursors in mouse bone marrow is described. In the presence of optimal erythropoietin concentrations mouse bone marrow cells have a greater specificity for mouse transferrin (950 CFU-E colonies/10(5) cells) than human transferrin (650 CFU-E colonies/10(5) cells). Optimal transferrin concentrations for both human and mouse transferrins were 1.3x10(-13)M and 1.3x10(-10)M corresponding to between 7.8x10(7) and 7.8x10(10) molecules/ml of culture. These concentrations are in excess of that calculated on a theoretical basis. Neither erythropoietic burst nor granulocyte/macrophage colony formation exhibited a dose dependent relationship for any of the transferrins employed, although higher colony numbers were obtained with mouse transferrin compared to human transferrin.

Animals↗
PubMed1984

In vitro and in vivo studies of iron delivery by human monoferric transferrins.

According to the Fletcher-Huehns hypothesis there exists a functional difference between the two iron-binding sites of transferrin. In this study we present the results of an evaluation of this hypothesis in vitro and in vivo with human pure monoferric transferrins obtained by preparative isoelectric focusing in granulated gels. The uptake of iron from monoferric transferrins TfFeC and FeNTf by erythroid bone marrow cells, hepatocytes and stimulated T-lymphocytes in vitro was equal, even when both monoferric transferrins were present together in the incubation medium. Ferrokinetic studies in vivo, performed with both pure monoferric transferrins, showed that transferrin TfFeC, as well as transferrin FeNTf, mainly deliver their iron to the erythron. As red cell 59Fe utilization, red cell iron turnover and other ferrokinetic parameters, obtained from this study, were identical too it is evident that both iron-binding sites of transferrin are functionally homogeneous in vivo, with respect to iron delivery.

Animals↗
PubMed1989

Presence of fucosylated triantennary, tetraantennary and pentaantennary glycans in transferrin synthesized by the human hepatocarcinoma cell line Hep G2.

Transferrin synthesized by a human hepatocellular carcinoma cell line Hep G2 (called Hep G2 transferrin) was purified from culture media by immunoaffinity chromatography on a rabbit anti-(human serotransferrin) IgG column. The eluted transferrin was then resolved into five peaks on a cation-exchange column using the fast protein liquid chromatography system. The major fraction, named Hep G2 transferrin fraction C, having a molecular mass of 82.5 kDa was found to be homogeneous in polyacrylamide gel electrophoresis and in concanavalin-A-affinity crossed immunoelectrophoresis. A comparative analysis of the molar carbohydrate composition of normal human serotransferrin and of Hep G2 transferrin fraction C shows an increase in the latter in the number of galactose and N-acetylglucosamine residues and in the presence of fucose, which is absent in normal transferrin. By a combination of methylation analysis and NMR spectroscopy, the primary structure of the oligosaccharide alditols released from Hep G2 transferrin fraction C by reductive alkaline cleavage has been established as triantennary, tetraantennary and pentaantennary N-acetyllactosaminic structures with fucose residues (alpha 1-3)-linked to peripheral N-acetylglucosamine residues. These results indicate that the increase in the number of antennae in transferrin glycans synthesized by the hepatocarcinoma cell line is much more pronounced than in liver diseases such as alcoholic cirrhosis and that, in addition, the malignant transformation of human liver induces the presence of fucose.

Carbohydrate Conformation↗