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PubMed1988

Growth-stimulating effect of ferric citrate on hybridoma cells: characterization and relation to transferrin function.

The growth of mouse hybridomas in the defined medium with ferric citrate at the optimum growth-stimulating concentration of 500 microM in place of transferrin is fully comparable with the growth in the medium with transferrin at the optimum concentration of 5 micrograms/ml. Experiments with monoclonal antibody to mouse transferrin receptor demonstrate that the growth-stimulating effect of ferric citrate is not based on the action of residual transferrin or the action of transferrin secreted by hybridoma cells. Such growth-stimulating effect is specific for iron compounds while other metal trace elements are ineffective. Hybridoma cells can absorb iron from medium containing iron salt without the presence of transferrin.

Animals↗
PubMed1988

Monoclonal antibodies to human transferrin: epitopic and phylogenetic analysis.

Monoclonal antibodies (MAbs) are useful reagents for the study of the structure and evolution of specific epitopes. Two MAbs of IgG1 isotype, Tf-1 and Tf-2, which bind human transferrin have been produced and characterized. Both specifically recognize transferrin on immunoblots of serum. Proteolytic digestion with papain or chymotrypsin destroys the epitope recognized by Tf-1 but not Tf-2, demonstrating that the MAbs recognize distinct epitopes. Both epitopes are not recognized after treatment with 2-mercaptoethanol, suggesting that disulfide bond dependent tertiary structure is necessary for epitope integrity. Removal of carbohydrate moieties by treatment with trifluoromethane sulfonic acid likewise results in loss of reactivity. Neither MAb reacts with transferrin of mouse, rabbit or bovine origin. Both were tested for reactivity to a total of ten primate transferrins and showed different patterns of reaction. Tf-2 recognized human, chimpanzee and gorilla transferrins, whereas Tf-1 reacted with all Old World monkeys and one of three New World monkeys tested. Thus, Tf-1 and Tf-2 recognize transferrin epitopes with differential phylogenetic conservation and which are dependent not only on primary aminoacid sequence, but also upon tertiary structure and glycosylation.

Antibodies, Monoclonal↗
PubMed1996

Wortmannin alters the transferrin receptor endocytic pathway in vivo and in vitro.

Treatment with the phosphatidylinositol 3-kinase inhibitor wortmannin promotes approximately 30% decrease in the steady-state number of cell-surface transferrin receptors. This effect is rapid and dose dependent, with maximal down-regulation elicited with 30 min of treatment and with an IC50 approximately 25 nM wortmannin. Wortmannin-treated cells display an increased endocytic rate constant for transferrin internalization and decreased exocytic rate constants for transferrin recycling. In addition to these effects in vivo, wortmannin is a potent inhibitor (IC50 approximately 15 nM) of a cell-free assay that detects the delivery of endocytosed probes into a common compartment. Inhibition of the in vitro assay involves the inactivation of a membrane-associated factor that can be recruited onto the surface of vesicles from the cytosol. Its effects on the cell-free assay suggest that wortmannin inhibits receptor sorting and/or vesicle budding required for delivery of endocytosed material to "mixing" endosomes. This idea is consistent with morphological changes induced by wortmannin, which include the formation of enlarged transferrin-containing structures and the disruption of the perinuclear endosomal compartment. However, the differential effects of wortmannin, specifically increased transferrin receptor internalization and inhibition of receptor recycling, implicate a role for phosphatidylinositol 3-kinase activity in multiple sorting events in the transferrin receptor's membrane traffic pathway.

Androstadienes↗
PubMed1980

Transferrin-dependent growth inhibition of yeast-phase Histoplasma capsulatum by human serum and lymph.

Nonspecific host defense mechanisms that may limit growth of yeast-phase Histoplasma capsulatum in vivo were examined using an in vitro system of cell-free liquid culture. Native human transferrin in serum and lymph, or purified transferrin added to serum-free medium, inhibited yeast replication 10- to 50-fold. Supplementation of serum with iron to complete or almost complete saturation of total iron-binding capacity neutralized inhibition. Substitution of Zn++, Mn++, or Cu++ for Fe++ did not affect inhibition. Neither complement nor antibody was a relevant factor. Results of culture in medium with unsaturated transferrin followed by replenishment with iron indicated that iron deprivation was either fungistatic or fungicidal, depending on the yeast strain and, in serum-free medium, on the iron content of transferrin. Transferrin-dependent fungistasis was associated with morphologic alteration of yeasts as determined by electron microscopy. Thus, susceptibility of yeast-phase H. capsulatum to iron starvation by unsaturated transferrin may contribute to their low virulence in vivo.

Antifungal Agents↗
PubMed1988

Relationships among iron absorption, percent saturation of plasma transferrin and serum ferritin concentration in humans.

The percent absorption of iron from four dietary sources was compared in 2018 human subjects with three indicators of iron status, serum ferritin concentration, percent saturation of plasma transferrin and iron absorption from a reference dose of ferrous sulfate. Higher correlation coefficients (r) were obtained by comparing dietary iron absorption with the reference dose absorption rather than with serum ferritin; for example, r = +0.61 and r = -0.38, respectively, for a meat and vegetable meal. However, in practice serum ferritin is almost as efficient as the reference dose absorption in estimating dietary iron absorption, because the 95% confidence limits calculated from the regression equations were very similar. The values of r calculated for iron absorption versus transferrin saturation were comparable to those obtained with the other indicators only in the range of transferrin saturation values below 25%, whereas in more iron-replete subjects (transferrin saturation greater than 25%), this correlation virtually disappeared. This indicates that, although both serum ferritin and transferrin saturation reflect iron status in iron-depleted subjects, the control of iron absorption in iron-replete subjects is more dependent on iron stores as reflected in the serum ferritin concentration than the percent saturation of transferrin.

Diet↗
PubMed1995

Brain iron, transferrin and ferritin concentrations are altered in developing iron-deficient rats.

To study the iron, transferrin, and ferritin distribution at subcellular levels in response to acute dietary iron deficiency, we tested the hypothesis that early post-weaning iron deficiency can change iron and iron regulatory protein concentrations in rat brain. Male Sprague-Dawley rats were fed diets containing either 2 or 35 micrograms iron/g for 2, 3 or 4 wk starting at 21 d of age. Brain iron, transferrin and ferritin concentrations in cytosolic and microsomal fractions of either whole brain or pons and cerebellum were then determined. After 14 d of dietary iron restriction, brain iron concentrations were 50% lower in the microsomal fraction and 30% lower in cytosol compared with controls. Brain cytosolic transferrin concentration almost doubled in the same animals. Brain ferritin concentration in fractions from rats fed the iron-deficient diet for 14 d was lower than in controls, but then remained fairly constant. Absolute brain weight and total brain protein contents were unaffected by iron restriction. This study extends previous research by demonstrating that the brain responds to changes in body iron status with a change in transferrin concentration. If the dietary restriction is quite severe, this adaptation is insufficient. This study also notes that brain ferritin decreases with decreasing body iron status, though it was less responsive than nonheme iron in liver. The concept that iron enters the brain through a highly regulated endocytotic process at the blood brain barrier, that undoubtedly involves the regulation of transferrin receptors in capillary endothelial cell, is supported by our observation of elevated transferrin concentrations in brain of iron-deficient rats.

Anemia, Iron-Deficiency↗
PubMed1995

Transferrin saturation and risk of cancer.

The authors examined the hypothesis that relatively high levels of transferrin saturation increase the risk of cancer. They studied a cohort of prepaid health plan members whose transferrin saturation levels were measured during the period 1969-1971 and who were followed for cancer through 1990. After the exclusion of 10 percent of the subjects who received treatment for one or more of six chronic conditions or who were pregnant when the measurement was made and persons who contributed less than 5 years of follow-up, the authors were left with 38,538 persons who were followed for an average period of 17.7 years. In women, a positive association was observed between transferrin saturation and risk of stomach carcinoma (> or = 34.5% compared with < or = 20.3%: relative risk (RR) = 3.5, 95% confidence interval (CI) 0.98-12). In men, transferrin saturation was inversely associated with risk of colon and rectal carcinoma (> or = 40.7% compared with < or = 26.0%: colon, RR = 0.62, 95% CI 0.35-1.1; rectum, RR = 0.30, 95% CI 0.08-1.1) and with non-Hodgkin's lymphoma (32.1-40.6% compared with < or = 26.0%: RR = 0.31, 95% CI 0.11-0.88; no cases observed with transferrin saturation > or = 40.7%). The authors did not find evidence that the risk of epithelial cancer (all sites combined) was related to transferrin saturation level or to iron deficiency (< or = 15%) or overload (> or = 60%).

Adult↗
PubMed1996

The effect of ethanol or hepatotoxin exposure on rat transferrin desialylation.

Serum carbohydrate-deficient transferrin (CDT) is being increasingly used as a biological indicator for excessive alcohol consumption. However, the mechanisms behind the changes in the carbohydrate moiety of transferrin are unclear, although they have been suggested to be mediated by acetaldehyde or liver damage. To study this, an animal model involving alterations in serum isotransferrin concentrations would be needed. The present work examined the changes in the carbohydrate moiety of transferrin in rats after different degrees of ethanol exposure, the effects of chronically elevated acetaldehyde levels, and also the changes, produced with liver toxins (galactosamine) and carbon tetrachloride). Ethanol was administered both in the drinking fluid and by intubation, reaching a dose of 11 g/kg/day over 7 weeks, or 16 g/kg/day over 4 weeks. Serum samples from rats maintained on high ethanol for 10 weeks by intragastric infusion were also analysed. Some rats simultaneously had cyanamide administered to elevate acetaldehyde levels. However, neither ethanol nor acetaldehyde had any effect on transferrin. Intraperitoneal galactosamine, but not carbon tetrachloride, induced transferrin desialylation. Thus, in the rat, neither chronic ethanol consumption nor elevated acetaldehyde induces changes in transferrin microheterogeneity.

Acetaldehyde↗
PubMed1987

A high level of transferrin mRNA in the liver of analbuminemic rats.

By means of immunological screening, a cDNA clone bearing the mRNA sequence for rat transferrin was isolated from a cDNA library of rat liver mRNA. The amounts of transferrin mRNA in livers of analbuminemic rats (NAR, Nagase analbuminemia rats) and normal rats were determined by RNA blot hybridization using a cloned transferrin cDNA probe. The level of transferrin mRNA in the NAR liver was about 1.7 times that in the normal rat liver. These findings suggest that the enhanced synthesis of transferrin in the NAR liver resulted from an increase in the transferrin mRNA level.

Animals↗
PubMed2002

A 3'-truncated transferrin messenger RNA is expressed in rat testicular germ cells.

Rat germ cells express a 0.9-kilobase (kb) message with a sequence similar to that of the 3' portion of mammalian transferrins. The sequence of this transcript, called hemiferrin, was considered unique, suggesting that it was encoded by a gene different from that of rat transferrin. Difficulties in conducting experiments using hemiferrin sequence primers led us to question the original sequence. Ribonuclease protection assays revealed that the hemiferrin sequence provided protection only for bovine sequences and not for rat mRNA. Conversely, a 3' rat transferrin sequence protected only rat liver and testis RNA sequences and not bovine sequences, indicating that the 0.9-kb transcript in germ cells is a truncated form of rat transferrin. Western analysis and immunoprecipitation of germ cell proteins metabolically radiolabeled in vitro and in vivo failed to detect a protein of the predicted size regardless of whether anti-rat transferrin or anti-hemiferrin antibodies were used. The findings suggest that a foreshortened transcript of the transferrin gene is produced in rat germ cells and that little or no protein is made from that transcript.

Animals↗
PubMed1999

The measurement of serum transferrin receptor.

The concentration of the soluble fragment of transferrin receptor in serum is an important new hematological parameter. Clinical and laboratory studies have shown that this serum form of the receptor reflects the total body mass of cellular transferrin receptor, 80% of which is contained in the erythroid marrow. The two disorders that result in an elevation in the serum transferrin receptor are anemias associated with enhanced erythropoiesis and tissue iron deficiency. The concentration of soluble transferrin receptor provides a useful quantitative measure of the erythroid marrow mass and thereby assists clinically in categorizing the type of anemia. The most important clinical use of the serum transferrin receptor is in determining the cause of iron deficient erythropoiesis (that is, identifying iron deficiency anemia whether it occurs alone or in the presence of the anemia of chronic disease). Present evidence supports the routine use of the serum transferrin receptor in the clinical evaluation of anemic patients.

Anemia↗
PubMed2002

Acetaldehyde-induced growth retardation and micro-heterogeneity of the sugar chain in transferrin synthesized by HepG2 cells.

BACKGROUND: A carbohydrate-deficient transferrin (CDT) is the most useful marker of alcohol abuse; however, the mechanism of production and the pathophysiologic roles of CDT remain obscure. The effects of alcohol and its metabolites on growth and proliferation, transferrin synthesis, and phosphomannomutase enzyme activity in a human hepatoblastoma, HepG2, were examined. METHODS: HepG2 cells were treated with either ethanol at 80 mM or acetaldehyde at 400 microM. Transferrin secreted by the cells was prepared from conditioned culture medium by single-step immunoaffinity column chromatography using a goat-specific antibody against human transferrin. Phosphomannomutase and some related enzyme activities in the cell extracts were determined. Reverse transcription-polymerase chain reaction analysis of phosphomannomutase mRNA expression was also determined in HepG2 cultured with or without acetaldehyde (400 microM). RESULTS: HepG2 cells usually synthesized and secreted transferrin with three separated bands: main broad bands estimated to be 78 to 82 kDa, 75 kDa, and 72 kDa. The last two bands were compatible with part or the entire N-glycans-deficient transferrin (CDT) from alcoholic liver damage. Increased secretion of CDT from HepG2 correlated well with the extent of growth retardation to the level of confluent cell density. The activity of phosphomannomutase also decreased with prolongation of cellular doubling time. Furthermore, acetaldehyde treatment at 400 microM accelerated the inhibitory effect of cell growth compared with nontreated cells, and this condition facilitated CDT secretion from HepG2 cells. Determination of the enzyme activity and mRNA expression indicated that acetaldehyde showed competitive type inhibition of phosphomannomutase activity but not suppression of phosphomannomutase gene expression. CONCLUSIONS: By culturing HepG2 cells with acetaldehyde containing media, growth inhibition-dependent increase of CDT showed good correlation with reduced enzyme activity of phosphomannomutase. Acetaldehyde facilitated growth retardation, inhibition of phosphomannomutase activity, and increased secretion of CDT. The HepG2 cell line is useful as an in vitro model to investigate the pathophysiologic state of alcoholic liver damage and mechanisms of production as well as the physiologic role of CDT.

Carcinoma, Hepatocellular↗
PubMed2004

Non-transferrin-bound iron in the serum of hemodialysis patients who receive ferric saccharate: no correlation to peroxide generation.

Intravenous iron (iv.Fe) is used to optimize response to recombinant human erythropoietin (r-HuEPO) in ESRD, but no consensus exists with respect to the best regimen to avoid transferrin "oversaturation," oxidative stress, and the occurrence of non-transferrin-bound iron (NTBI). Iv.Fe was stopped for 1 wk in 35 hemodialysis (HD) patients who were routinely receiving iv.Fe and r-HuEPO. The iv.Fe group received 100 mg of ferric saccharate (Venofer) at the end of the first HD session, whereas the time-control group was treated under the same conditions but received no iv.Fe. Serum samples were taken before the first HD session, immediately and 60 min after iv.Fe administration, and before the next HD session. Sera were analyzed for NTBI and peroxides; transferrin saturation was analyzed by urea-PAGE and Western blot. In an in vitro model system with HepG2 cells, the effects of ESRD serum on the labile iron pool (LIP) were assayed using the fluorescence calcein assay. NTBI significantly increased after iv.Fe-administration and returned to baseline values before the next HD-session. There was a shift from apo- to monoferric transferrin, but no "oversaturation" of transferrin after iv.Fe-treatment. Peroxides increased in both groups after HD. Hemodialysis decreased bioavailable iron for the LIP in HepG2-cells, whereas serum of iv.Fe-treated HD patients highly increased the LIP in these cells. A total of 100 mg of iv.Fe led to NTBI generation but not to an oversaturation of transferrin. Peroxide concentrations significantly increased during HD but were not correlated to iv.Fe administration and seemed to result from other sources of oxidative stress related to HD. NTBI can enter liver cells and increase the potentially harmful LIP.

Blotting, Western↗
PubMedDate not supplied

Iron status of children with phenylketonuria undergoing nutrition therapy assessed by transferrin receptors.

PURPOSE: The purpose of the study was to determine the incidence of iron deficiency in children undergoing therapy for phenylketonuria using serum transferrin receptor and ferritin concentrations. METHODS: A 1-year study was conducted in 37 children 2 <13 years old with phenylketonuria (8 fed Periflex [Group I], 15 fed Phenex-2 Amino Acid-Modified Medical Food [Group II], and 14 fed Phenyl-Free [Group III]). Hemoglobin, hematocrit, serum transferrin receptor, and ferritin concentrations were assessed at baseline and 12 months and intakes of protein, iron, and vitamin C were evaluated at baseline and at 3-month intervals. Transferrin receptor and ferritin concentrations were analyzed for group differences by analysis of variance. RESULTS: Mean protein, iron, and vitamin C intakes of all 3 groups of children were greater than Recommended Dietary Intakes for age. Only 2 of 60 3-day diet diaries of Group II children failed to contain 100% of Recommended Dietary Intakes for iron during study. The following number of children had iron status indices outside reference ranges at study end: 7 children, transferrin receptor/ferritin ratios; 4 children, transferrin receptors; 2 children, hematocrit; 1 child, ferritin. No correlation was found between iron intake and any index of iron status. CONCLUSIONS: The transferrin receptor/ferritin ratio appeared to be the most sensitive index of iron deficiency in this study. Reasons for iron deficiency with greater than recommended iron intakes by children with phenylketonuria may be multiple. Early assessment and therapy of iron deficiency may improve cognitive and behavioral outcomes of children with PKU.

Analysis of Variance↗
PubMed1996

Conservation and antigenic cross-reactivity of the transferrin-binding proteins of Haemophilus influenzae, Actinobacillus pleuropneumoniae and Neisseria meningitidis.

Haemophilus influenzae acquires iron from the iron-transporting glycoprotein transferrin via a receptor-mediated process. This involves two outer-membrane transferrin-binding proteins (Tbps) termed Tbp1 and Tbp2 which show considerable preference for the human form of transferrin. Since the Tbps are attracting considerable attention as potential vaccine components, we used transferrin affinity chromatography to examine their conservation amongst 28 H. influenzae type b strains belonging to different outer-membrane-protein subtypes as well as six non-typable strains. Whole cells of all type b and non-typable strains examined bound human transferrin; whilst most strains possessed a Tbp1 of approximately 105 kDa, the molecular mass of Tbp2 varied from 79 to 94 kDa. Antisera raised against affinity-purified native H. influenzae Tbp1/Tbp2 receptor complex cross-reacted on Western blots with the respective Tbps of all the Haemophilus strains examined. When used to probe Neisseria meningitidis Tbps, sera from each of four mice immunized with the Haemophilus Tbp1/2 complex recognized the 68 kDa Tbp2 of N. meningitidis strain B16B6 but not the 78 kDa Tbp2 of N. meningitidis strain 70942. Serum from one mouse also reacted weakly with Tbp1 of strain B16B6. Apart from a weak reaction with the Tbp2 of a serotype 5 strain, this mouse antiserum failed to recognize the Tbps of the porcine pathogen A. pleuropneumoniae. However, a monospecific polyclonal antiserum raised against the denatured Tbp2 of Neisseria meningitidis B16B6 recognized the Tbps of all Haemophilus and Actinobacillus strains examined. Since H. influenzae forms part of the natural flora of the upper respiratory tract, human sera were screened for the presence of antibodies to the Tbps. Sera from healthy adults contained antibodies which recognized both Tbp1 and Tbp2 from H. influenzae but not N. meningitidis. Convalescent sera from meningococcal meningitis patients contained antibodies which, on Western blots, recognized the Tbps2s of both pathogens. These data demonstrate the existence of shared epitopes on the Tbps of H. influenzae, N. meningitidis and A. pleuropneumoniae despite their transferrin species specificity.

Actinobacillus pleuropneumoniae↗
PubMed2003

Structure of diferric hen serum transferrin at 2.8 A resolution.

Hen serum transferrin in its diferric form (hST) has been isolated, purified and the three-dimensional structure determined by X-ray crystallography at 2.8 A resolution. The final refined structure of hST, comprising 5232 protein atoms, two Fe(3+) cations, two CO(3)(2-) anions, 54 water molecules and one fucose moiety, has an R factor of 21.5% and an R(free) of 26.9% for all data. The structure has been compared with the three-dimensional structure of hen ovotransferrin (hOT) and also with structures of some other transferrins, viz. rabbit serum transferrin (rST) and human lactoferrin (hLF). The overall conformation of the hST molecule is essentially the same as that of other transferrins. However, the relative orientation of the two lobes, which is related to the species-specific receptor-recognition property of transferrins, has been found to be different in hST from that in hOT, rST and hLF. On the basis of superposition of the N lobes, rotations of 5.8, 16.9 and 11.3 degrees are required to bring the C lobes of hOT, rST and hLF, respectively, into coincidence with that of hST. A number of additional hydrogen bonds between the two domains in the N and C lobes have been identified in the structure of hST compared with that of hOT, which indicate a greater compactness of the lobes of hST than those of hOT. Being products of the same gene, hST and hOT have 100% sequence identity and differ only in the attached carbohydrate moiety. On the other hand, despite having similar functions, hST and rST have only 51% sequence similarity. However, the nature of the interdomain interactions of hST are closer to rST than to hOT. A putative carbohydrate-binding site has been identified in the N lobe of hST at Asn52 and a fucose molecule could be modelled at the site. The variations in interdomain and interlobe interactions in hST, together with altered lobe orientation with respect to hOT, rST and hLF, which are the representatives of the other subfamily of transferrins, are discussed.

Amino Acids↗
PubMed1991

Intestinal transferrin receptors and iron absorption in the neonatal rat.

The transferrin receptor is a major protein found on the basolateral membranes of intestinal epithelial cells, yet its possible role in intestinal iron metabolism and also in iron absorption is unclear. We have studied intestinal transferrin receptor expression during the peri- and postnatal development of the small intestine of the rat using immunohistochemistry with a monoclonal antibody to the rat receptor. Two major changes in transferrin receptor expression in the developing small intestine were found, a decrease in receptor expression associated with birth, and an increase at the time of weaning. Around the time of weaning there was a large decrease in iron absorption, but there was no direct correlation between absorption and transferrin receptor expression. However, at both birth and weaning there were major changes in intestinal cell kinetics, and the distribution of receptor correlated well with the distribution of proliferating cell populations. In addition, as the intestinal epithelial cells differentiated and stopped dividing, there was a redistribution of transferrin receptors from the cell surface to intracellular sites. These data suggest that the most likely role of the transferrin receptor in the neonatal intestine is in the supply of iron to the developing epithelial cells in the crypts, and that the receptor does not play a direct role in iron transit across the intestinal epithelium.

Aging↗
PubMed1992

Effect of transferrin, lactoferrin and chelated iron on human T-lymphocytes.

The effect of different forms of iron and iron-binding proteins on the proliferative response of human lymphocytes to phytohaemagglutinin (PHA) has been studied. Transferrin enhanced proliferation, the effect being proportional to the degree of iron saturation up to 100%, but decreased if additional iron was present. The lipophilic complex ferric pyridoxal isonicotinoyl hydrazone (FePIH) also enhanced proliferation, but the hydrophilic complex ferric nitrilotriacetate (FeNTA) was inhibitory. Fe-lactoferrin could not substitute for Fe-transferrin, although iron-free (apo) lactoferrin abrogated the inhibitory effect seen when iron levels exceed the binding capacity of transferrin. Lymphocyte ferritin levels increased 4-fold as the iron saturation of transferrin increased from 0 to 90% but no further increase was seen at higher iron levels, suggesting that lymphocytes are poorly equipped to detoxify excess iron through stimulation of ferritin synthesis. The effect of iron on the CD4:CD8 ratio after 72 h culture with PHA was also examined. The ratio was approximately 2:1 for cells cultured with transferrin at iron saturations between 0 and 75%, with FePIH, or without either, but decreased to 1.1:1 when cells were cultured in the presence of FeNTA, regardless of whether or not saturated Fe-transferrin was present. These results show that iron can affect lymphocyte proliferation and subset ratios in different ways according to the form and amount present, and may help to explain some of the immunological disturbances associated with iron overload.

Adult↗