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PubMed1988

Transferrin receptor expression in human hepatocellular carcinoma: an immunohistochemical study of 34 cases.

Using a panel of five monoclonal anti-transferrin receptor antibodies, we investigated the transferrin receptor expression in 34 human hepatocellular carcinomas of Belgian (n = 6), Italian (n = 7) and South African (n = 21) origin. For comparison the tumours were also stained with the monoclonal antibody BK 19.9, recognizing an antigen biochemically similar to the transferrin receptor, and with a monoclonal antibody against the epidermal growth factor receptor. Hepatocellular carcinomas express large amounts of transferrin receptors as demonstrated by the intense transferrin receptor immunostaining in 33/34 cases. Differences in staining pattern between and within the tumours were not related to the degree of tumour differentiation, nor to the origin or race of the patient. In 15 cases which included non-tumoural tissue, the tumour was more intensely stained than the surrounding liver parenchyma. The BK 19.9 immunoreactivity was generally weaker and mainly involved stromal cells, except in three cases where an intense staining of the tumour cells was seen. The epidermal growth factor receptor staining was also weaker and only in four cases was the immunoreactivity of the tumour stronger than the surrounding parenchyma. Demonstration of the transferrin receptor may be useful for the detection of malignant foci in liver biopsies. This may be of particular interest in the histological investigation of minute hepatocellular carcinomas.

Biopsy↗
PubMed1989

Twenty-four hour variation of transferrin saturation in treated and untreated haemochromatosis homozygotes.

We studied 43 haemochromatosis homozygotes and seven normal individuals to test the hypothesis that there is an almost continuous relative deficiency of apotransferrin in treated and untreated homozygotes. Transferrin saturation was measured at 2-h intervals for 24 h while all subjects ate their usual diet. Subjects with haemochromatosis were separated into four groups based on sex and whether or not they had been iron-depleted. Nineteen treated and 11 untreated male homozygotes had mean transferrin saturation values of 70 and 81%, respectively. Five treated and eight untreated female homozygotes had mean transferrin saturation values of 71 and 69%. Normal subjects had mean transferrin saturation values of 29% (3 males) and 21% (4 females). These data demonstrate continuously high transferrin saturation values, greater than 69% in most treated and untreated male and female homozygotes, resulting in hepatic iron accumulation of non-transferrin-bound iron from the portal circulation.

Bloodletting↗
PubMed1988

Characterization of the human transferrin and lactoferrin receptors in Haemophilus influenzae.

The expression of human transferrin and lactoferrin binding activity in Haemophilus influenzae, detected by a binding assay using human transferrin or lactoferrin conjugated to peroxidase, was regulated by the level of available iron in the medium. Transferrin binding activity was present in all H. influenzae isolates tested but not detected in other Haemophilus species or in species of Pasteurella or Actinobacillus. Lactoferrin binding activity was only detected in 1/15 H. influenzae isolates tested. The transferrin and lactoferrin receptors were shown to be specific for the respective human proteins by means of a competition binding assay. Competition binding assays also showed that iron-loaded transferrin was more effective at blocking the transferrin receptor than apotransferrin, but no differences in receptor blocking were observed between iron-loaded lactoferrin and apolactoferrin.

Animals↗
PubMed1984

Monoclonal antibodies to a purified human transferrin receptor.

BALB/c mice were injected with an affinity-chromatography-purified placental transferrin receptor preparation. Spleen cells were fused with NS-1 myeloma cells. Sixteen hybrids producing monoclonal antibodies specific for the transferrin receptor and two hybrids specific for transferrin were identified by radioimmunoassay (RIA). Five hybrids were selected for cloning on the basis of antibody specificity and affinity. None of the antibodies inhibited the binding of transferrin to K562 cells. The binding of antibody ID9 to K562 cells was partially inhibited by transferrin or a polyclonal goat anti-transferrin receptor antiserum. Of the five antibodies, two (IIB6 and IIB2) reacted only with the purified receptor and solubilized cells and not with whole cells. The other three antibodies, when tested with normal human cells and leukaemia and tumour cell lines, showed identical reaction patterns. The antibodies precipitated a glycoprotein from K562 cells with an apparent molecular weight of 94,000, estimated from sodium dodecyl sulphate-polyacrylamide gel electrophoretograms run under reducing conditions, and a molecular weight of 188,000 when run under unreduced conditions. All antibodies have a high affinity with Ka values ranging from 1.44 X 10(9) to 3.56 X 10(10) (l/mol). The antigen precipitated by all five antibodies showed identical peptide maps after partial proteolytic digestion.

Antibodies, Monoclonal↗
PubMed1977

The molecular components of human transferrin type C.

Immunologically pure human transferrin type C (TfC) was isolated from the plasmas of 11 individual healthy donors. After conversion into the 2Fe-form, the preparations were analysed by polyacrylamide gel electrophoresis and chromatography on DEAE-cellulose. In all samples studied by either method the presence of three components, designated A, B and C, was observed. Calculations from eight chromatograms yielded the following relative proportions for the components: A:6%, B:62% and C:32%. The quantity of iron bound played no role in this chromatographic resolution. The components were immunologically identical but their sialic acid content increased inthe order of A less than B less than C. The presence of galactose as an ultimate residue of the oligosaccharide chains in TfC component A was confirmed by a biological test. This observation together with the results of earlier analyses for hexose, hexosamine and galactose in the subfractions from Behringwerke human transferrin, suggests that sialic acid is probably the only variable among TfC components A, B and C. Loss of sialic acid from component C during the isolation of TfC was excluded as an explanation for the presence of the other two components. The electrophoretic appearance of TfC samples from five patients with liver disease (chronic active hepatitis, cirrhosis or alcoholic liver) did not noticeably differ from that of TfC FROM HEALTHY PERSONS. Baboon transferrin resembles TfC with respect to sialic acid heterogeneity. This species was therefore studied to decide whether sialic acid is gradually lost from transferrin in the circulation or whether transferrin is not fully sialylated before discharge from the hepatocyte. Using DEAE-cellulose chromatography no difference was found between baboon transferrin molecules which were less than 6h old and those which had a mean age of 8.9 days. By inference it is suggested that the reason for the multiplicity of TfC is also likely to be biosynthetic.

Adult↗
PubMed1978

Synthesis and secretion of transferrin by cultured mouse hepatoma cells.

The mouse hepatoma cell (Hepa-1) in tissue culture has been shown to synthesize and secrete three electrophoretically distinct transferrins. Each of these forms of transferrin has a molecular weight of 77,000, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The concentration of each form is indicated by its staining intensity, which is highest in the form with the fastest mobility and lowest in the form with the slowest mobility. The relative rate of transferrin synthesis has been determined in log-phase and stationary-phase cells; the data indicate that the relative rate of synthesis increases twofold in stationary-phase cells. When the incorporation of [3H]leucine into transferrin reaches steady state, the rate of secretion is equal to the rate of synthesis; the rate of secretion also increases twofold in stationary-phase cells. Our studies also show that transferrin synthesis accounts for 0.98% of the total protein synthesis in log-phase cells and for 1.8% in stationary-phase cells. This is the level of synthesis that has been determined by in vivo studies. We conclude that after continuous culture for several years these hepatoma cells have maintained one of the characteristics of the differentiated liver cell, namely, the ability to synthesize and secrete transferrin.

Carcinoma, Hepatocellular↗
PubMed1976

Gel isoelectric focusing of human-serum transferrin.

Analysis of human serum transferrin on gel isoelectric focusing resolved this iron-transport protein into two iron-containing components which were identified by the use of radioactively labelled iron and iron-specific stain. These two components were found to be monoferric transferrin (Fe-transferrin) and diferric transferrin (Fe2-transferrin) with isoelectric points of 5.6 and 5.2 respectively. The estimation of the relative proportions of these two components in serum did not correspond to the calculated theoretical ratio based on random binding of iron to the two binding sites of transferrin. However, the analysis of partially resatured apotransferrin gave a ratio corresponding to a random distribution of iron. The significance of these results is discussed.

Apoproteins↗
PubMed1987

Differences among five main forms of serum transferrin.

Five forms of human serum transferrin with different isoelectric points were purified by isoelectric focusing in agarose gels. They constitute a set of main transferrin forms in serum of healthy individuals. Their relative proportions are changed in serum from alcoholic individuals, where the more basic of these forms are increased. Tryptic peptides of all forms were compared by high performance liquid chromatography (HPLC) patterns (fingerprint analysis). Two major differences were detected between corresponding tryptic peptides of the five transferrin forms. Some minor differences were also noticed. The corresponding peptides were purified from the main form and analyzed for total composition and amino acid sequence. The peptides with the major differences between the forms were found to be the two with the glycosylation attachment at positions 413 and 611. A minor peptide difference between the transferrin forms contains a product that is explained by incomplete stoichiometry in cleavage of the peptide bond at positions 217-218. Successive loss of sialic acid is compatible with the presence of different transferrin forms, and our results indicate that the main differences between the serum transferrin forms from healthy and alcoholic individuals are in successive changes of the carbohydrate chains attached at positions 413 and 611.

Amino Acid Sequence↗
PubMed1984

Non-transferrin plasma iron in beta-thalassaemia/Hb E and haemoglobin H diseases.

Non-transferrin plasma iron concentrations were determined in 45 normal controls and in 37 patients with Hb H disease and 104 patients with beta-thalassaemia/Hb E disease. This revealed that non-transferrin plasma iron exists in cases with severe iron overload, more striking in beta-thalassaemia/Hb E than in Hb H disease. Non-transferrin plasma iron is associated with higher transferrin iron saturation and higher plasma ferritin levels. The most striking finding was the significantly higher non-transferrin plasma iron in splenectomized patients with beta-thalassaemia/Hb E disease than in the non-splenectomized patients. In view of the potential toxicity of non-transferrin iron, this fraction of iron may be responsible for tissue damage in these patients especially after splenectomy.

Hemoglobin E↗
PubMed1990

Expression of Neisseria meningitidis iron-regulated outer membrane proteins, including a 70-kilodalton transferrin receptor, and their potential for use as vaccines.

The iron-regulated proteins (IRPs) of five group B meningococcal strains expressing class 2 outer membrane proteins were compared with those of five strains expressing class 3 proteins. Three to four high-molecular-weight IRPs were expressed by each strain, but their molecular sizes varied between strains and were not related to class 2 or 3 protein expression. Transferrin and hemoglobin could be used as a sole iron source. By using anti-human transferrin antibodies, it was shown that meningococcal cells and purified outer membranes bound transferrin. Growth under conditions of iron limitation caused a several-fold increase in the amount of transferrin bound to the cell surface. The transferrin-binding protein was detergent solubilized from outer membranes and partially purified. The isolated protein bound human transferrin and had an apparent molecular mass of 70 kilodaltons. To evaluate the potential of vaccines containing IRPs, we prepared outer membrane vaccines from strains M986-NCV-1 (M986) (--:2a: P1.2) and 44/76-M25 (44/76) (--:15:P1.15) grown to fully express their IRPs. Both vaccines induced significant anti-IRP antibodies as measured by enzyme immunoassay and by Western immunoblot with both M986 and 44/76 outer membranes. By Western blot analysis, the M986 vaccine induced antibodies to two different IRPs, one of which was shared with 44/76. Since the IRPs are major in vivo-expressed outer membrane proteins and are required for survival in vivo, these proteins should be evaluated for their usefulness in a group B meningococcal vaccine.

Animals↗
PubMed1991

Relative availability of transferrin-bound iron and cell-derived iron to aerobactin-producing and enterochelin-producing strains of Escherichia coli and to other microorganisms.

A method is described for determination of the relative availability of transferrin-bound iron and cell-derived iron to microbial iron-scavenging mechanisms. This involved incubation of parallel cultures of microorganisms in dialysis tubes placed in RPMI 1640 tissue culture medium containing 30%-iron-saturated transferrin and K562 erythroleukemia cells. In one culture the transferrin was labelled with 59Fe and in the other the cells were labelled, and the relative uptake of radioiron by the microorganisms determined. The results showed that Staphylococcus epidermidis and Staphylococcus aureus acquired iron predominantly from cells, while Candida albicans and the enteropathogenic Escherichia coli NCTC 8623 tended to acquire iron from transferrin. E. coli K-12 strains W3110 and LG1705, which (like NCTC 8623) produce the siderophore enterochelin but not aerobactin, acquired predominantly transferrin-bound iron, whereas the related E. coli strains LG1315 and LG1628, which produce aerobactin but not enterochelin, showed a preference for cell-derived iron. When the cells were incubated in the presence of 59Fe-labelled transferrin and 55Fe-labelled ferritin, no difference in relative availability of iron to E. coli was observed, suggesting that differences in the ability of aerobactin and enterochelin to remove iron from intracellular ferritin were not responsible for this preference. These results may help to explain why production of aerobactin, despite its relatively low affinity for iron, is more closely associated with invasiveness in E. coli than is enterochelin production. Reduced availability of cell-bound iron during inflammation may contribute to antimicrobial defenses.

Candida albicans↗
PubMed1992

Evidence for in vivo expression of transferrin-binding proteins in Haemophilus influenzae type b.

Haemophilus influenzae type b acquires transferrin-bound iron via a siderophore-independent mechanism involving direct contact between the human iron-binding glycoprotein and the bacterial cell surface. Evidence has accumulated to show that the transferrin receptor consists of at least two iron-regulated outer membrane transferrin-binding proteins (TBPs), of which one has a molecular mass of around 100 kDa (TBP1) and the other has a molecular mass of 60 to 90 kDa (TBP2). In H. influenzae type b strain Eagan, proteins of 76, 90, and 107 kDa appear to be involved in transferrin binding. To determine whether these TBPs are expressed during growth in vivo, strain Eagan was recovered without subculture from the intraperitoneal cavities of infected infant rats. By using a dot blot assay, outer membranes prepared from these in vivo-grown bacteria, unlike those grown in iron-sufficient broth, bound human transferrin and produced the 76-, 90-, and 107-kDa TBPs. Immunoblotting experiments using convalescent sera from infected rats also revealed the presence of antibodies to the 76- and 90-kDa strain Eagan TBPs. In addition, convalescent sera from three of four patients recovering from H. influenzae type b meningitis contained antibodies to the 90- and 105-kDa TBPs of the corresponding infecting strain. Furthermore, fresh clinical isolates of H. influenzae type b recovered from blood and cerebrospinal fluid showed constitutive expression of the TBPs, which became iron regulated only after prolonged in vitro subculture on iron-sufficient medium. This contrasted with the laboratory-adapted Eagan strain, in which the TBPs remained iron regulated even after animal passage. These findings indicate that the H. influenzae type b transferrin receptor is expressed during experimental animal and human infections.

Animals↗
PubMed1993

Ability of Pseudomonas pseudomallei malleobactin to acquire transferrin-bound, lactoferrin-bound, and cell-derived iron.

The ability of malleobactin to mobilize iron from transferrin and lactoferrin was examined in an equilibrium dialysis assay in the absence of bacteria. Malleobactin was capable of removing iron from both transferrin and lactoferrin at pH values of 7.4, 6.0, and 5.0. However, the levels of iron mobilization were greater for transferrin than for lactoferrin at all the pH values used in the assay. The ability of Pseudomonas pseudomallei to acquire iron from 30% iron-saturated transferrin and K562 human erythroleukemic cells was compared in parallel cultures as described previously (J. H. Brock, P. H. Williams, J. Liceaga, and K. G. Woldridge, Infect. Immun. 59:3185-3190, 1991). P. pseudomallei U7 tended to acquire iron from transferrin. In contrast, P. aeruginosa PAO and P. cepacia Pc275C acquired iron from both sources. P. cepacia H1721, which does not produce detectable siderophores, but can utilize malleobactin, pyochelin, and azurechelin as iron sources, was used in a similar experiment. Addition of malleobactin resulted in iron uptake only from transferrin, whereas pyochelin and azurechelin promoted iron uptake from both sources. When the siderophores were incubated with K562 cells alone, malleobactin was less efficient at removing iron from cells than pyochelin and azurechelin. It was also determined that malleobactin was less effective in binding to or entering cells than pyochelin and azurechelin. These results suggest that malleobactin can acquire iron more effectively from host proteins than from cellular sources. Pyochelin and azurechelin can acquire cell-derived iron in addition to iron bound to host proteins.

Burkholderia pseudomallei↗
PubMed1986

Estrogen regulation of the avian transferrin gene in transgenic mice.

The intact chicken transferrin gene was microinjected into fertilized mouse eggs, and the resulting transgenic animals were used to produce lines of mice containing integrated copies of the chicken gene. The levels of expression of the chicken gene were quantitated in various tissues, and the response of the gene to estrogen stimulation was measured after chronic or acute estrogen exposure. Two of the three mouse lines studied maintained stable levels of expression in successive generations of offspring, and the third line had two- to threefold-higher levels in offspring than in the original parent. In the third line, the original transgenic parent was found to be a mosaic. The chicken transferrin gene was expressed at 10- to 20-fold-higher levels in liver than in any other tissue; however, the levels of chicken transferrin mRNA in kidney were higher than expected, indicating that the tissue specificity was only partial. In all three lines, the foreign gene was induced by estrogen administration. After 10 days of estrogen administration, there was a twofold increase in both transferrin mRNA and transcription of the chicken transferrin gene. A single injection of estradiol led to a fourfold increase in transferrin mRNA synthesis at 4h. As a control the levels of mouse albumin were measured, and both the level of albumin mRNA and its rate of transcription declined about twofold after estrogen administration. Our results indicate that the intact chicken gene with 2.2 kilobases of 5' flanking sequence contains signals for both tissue specificity and steroid regulation that can be recognized in mice.

Animals↗
PubMed1990

Carbohydrate deficient serum transferrin in a new systemic hereditary syndrome.

Four patients with a new, inherited, complex developmental deficiency syndrome were studied. The syndrome affects the central and peripheral nervous system, and also the retina, liver, bone, adipose tissue, and genital organs. Abnormalities of glycoproteins, glycopeptide hormones, and lipids have been found in serum from these patients, the most pronounced being increased cathodal forms of transferrin. Isoforms of serum transferrin were therefore analysed qualitatively and quantitatively by isoelectric focusing and isocratic anion exchange chromatography, and the carbohydrate composition was determined in transferrin isolated by immune affinity chromatography. All the patients had about tenfold raised serum concentrations of isotransferrins with higher isoelectric points than normal. Similar findings, though less pronounced, were made in all the fathers and in one of the mothers. Half the transferrin in the patients was constantly present in two principal abnormal cathodal forms in approximately equal amounts. Carbohydrate determinations in purified transferrin showed quantitatively similar deficiencies of sialic acid, galactose, and N-acetylglucosamine, the mannose content being normal. The results suggest that either two or all of the normally four terminal trisaccharides in transferrin may be missing. A defect in the synthesis or catabolism, or both, of this trisaccharide, which is common to many secretory glyco-conjugates, is likely. Apart from providing a quantitative diagnostic method, the present findings may serve as a basis for further studies of the metabolic deficiency in this syndrome.

Biomarkers↗
PubMed1984

Distribution of ferritin, transferrin and lactoferrin in breast carcinoma tissue.

An immunoperoxidase staining technique was used for detecting three major iron binding proteins (ferritin, transferrin and lactoferrin) in 40 breast carcinoma cases and six benign breast proliferative lesions. Ferritin staining was detected mainly in connectival stroma and in histiocytes surrounding neoplastic cells. Few and faint ferritin positivities were also detected in neoplastic cells of 20 carcinoma cases. Transferrin was found inconsistently in myoepithelial cells surrounding normal ductules, or around neoplastic ducts of ductal in situ carcinoma. In eight carcinoma cases, transferrin staining was also positive in neoplastic cells. Lactoferrin was detected only in normal breast epithelial cells and in benign breast proliferative lesions. These immunohistochemical findings may suggest that raised serum ferritin concentrations in breast carcinoma patients might be attributed to stromal reaction rather than to tumour synthesis. Transferrin staining of neoplastic cells in these carcinoma cases appears to be very intriguing, particularly since transferrin is considered an obligate requirement for growing cells, and transferrin receptors have been demonstrated only in dividing cells. On the basis of the immunohistochemical data, lactoferrin might be used as a pointer to benign lesions.

Adenocarcinoma, Mucinous↗
PubMed1978

Effect of transferrin saturation on iron delivery in rats.

Studies were carried out in rats to evaluate the release of iron from monoferric and diferric transferrin. Isoelectric focusing was carried out on plasma tagged at low and high saturations, and it was shown that these represented primarily monoferric and diferric transferrin, respectively. In vivo studies with these tagged plasmas were carried out on normal, iron-deficient, and hypertransfused rats. In all three groups there was a greater in vivo uptake of iron from diferric transferrin by all tissues monitored. Though the amount varied in different animals, the ratio of uptake between diferric and monoferric transferrin iron varied between 1.56 and 2.10 in the erythron and between 2.38 and 2.65 in the liver. These studies indicate that changes in transferrin saturation, by changing the proportion of monoferric to diferric transferrin iron, changed the amount of iron released to tissues.

Animals↗
PubMed1980

Transferrin receptors on the human placental microvillous membrane.

A preparation of microvillous membrane vesicles from human placental syncytiotrophoblast binds transferrin to specific transferrin receptors. Transferrin binding to placental receptors is rapid, saturable, reversible, and specific. Approximately 2.5 X 10(13) receptors are present per milligram of membrane protein; the apparent association constant of transferrin for the placental receptor is 2.2 X 10(7) X M-1. No evidence for removal of iron from transferrin bound to intact membrane receptors was observed in these studies. Nonionic detergent solubilization and partial purification of the microvillous membrane transferrin receptor were carried out with preservation of the functional properties of the receptor.

Female↗