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International Journal of Hematology

, Volume 76, Issue 3, pp 213–218 | Cite as

Transferrin Receptor in Tissue and Serum: Updated Clinical Significance of Soluble Receptor

Progress in hematology

Abstract

The transferrin receptor is an essential component of cellular uptake of iron, and it binds to serum transferrin. Recently, 2 different types of transferrin receptors have been recognized: transferrin receptor (TfR or transferrin receptor 1) and transferrin receptor 2. Most cells possess a ubiquitous system controlling the biosynthesis of TfR at the posttranscriptional level to avoid excess iron influx into the cells through TfR. During the process of recycling of transferrin receptors, some are shed and appear as soluble or serum transferrin receptors. Measurement of serum transferrin receptor is a new marker of iron metabolism that reflects body iron stores and total erythropoiesis. It has been shown that serum transferrin receptor to ferritin ratios have significant predictive value for differentiating iron deficiency anemia from noniron deficiency anemia, such as anemia of chronic disorders, whereas serum ferritin is the only significant independent predictor of iron deficiency anemia.

Key words

Transferrin receptor Cellular iron uptake Iron-responsive element Soluble transferrin receptor Anemia of chronic disorder 

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References

  1. 1.
    Kawabata H, Yang R, Hirama T, et al. Molecular cloning of transferrin receptor 2: a new member of the transferrin receptor-like family.J Biol Chem. 1999;274:20826–20832.CrossRefPubMedGoogle Scholar
  2. 2.
    Shih YJ, Bayness RD, Hudson BG, Flowers CH, Skikne BS, Cook JD. Serum transferrin receptor is a truncated form of tissue receptor.J Biol Chem. 1990;265:19077–19081.PubMedGoogle Scholar
  3. 3.
    Kohgo Y, Nishisato T, Kondo H, Tsushima N, Niitsu Y, Usushizaki I. Circulating transferrin receptor in human serum.Br J Haematol. 1986;64:277–281.CrossRefPubMedGoogle Scholar
  4. 4.
    Allen J, Backstrom KR, Cooper JA, et al. Measurement of soluble transferrin receptor in serum of healthy adults.Clin Chem. 1998;44: 35–39.PubMedGoogle Scholar
  5. 5.
    Jandl JH, Katz JH. The plasma-to-cell cycle of transferrin in iron utilization.J Clin Invest. 1963;42:314.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Uchida T. Overview of iron metabolism.Int J Hematol. 1995;62: 193–202.CrossRefPubMedGoogle Scholar
  7. 7.
    Dautry-Varsat A, Chechanover A, Lodish HF. pH and the recycling of transferrin during receptor-mediated endocytosis.Proc Natl Acad Sci U S A. 1983;80:2258–2262.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Levy JE, Jin O, Fujiwara Y, Kuo F, Andrews NC. Transferrin receptor is necessary for development of erythrocytes and the nervous system.Nat Genet. 1999;21:396–399.CrossRefPubMedGoogle Scholar
  9. 9.
    Johnston RM. The Jeanne Manery-Fisher Memorial Lecture 1991. Maturation of reticulocytes: formation of exosome as a mechanism for shedding membrane proteins.Biochem Cell Biol. 1992;70: 179–190.CrossRefGoogle Scholar
  10. 10.
    Shintani N, Kohgo Y, Kato J, et al. Expression and extracellular release of transferrin receptor during peripheral erythroid progenitor cell differentiation in liquid culture.Blood. 1994;83: 1209–1215PubMedGoogle Scholar
  11. 11.
    Jing SQ, Trowbridge IS. Identification of the intermolecular disulfide bonds of the human transferrin receptor and its lipid-attachment site.EMBO J. 1987;6:327–331.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Iacopetta BJ, Rotehnberger S, Kuhn LC. A role for the cytoplasmic domain in transferrin receptor sorting and coated pit formation during endocytosis.Cell. 1988;12:485–489.CrossRefGoogle Scholar
  13. 13.
    Gross CN, Irrinki A, Feder JN, Enns CA. Co-trafficking of HFE, a nonclassical major histocompatibility complex class I protein, with the transferrin receptor implied a role in intracellular iron.J Biol Chem. 1998;273:22068–22074.CrossRefPubMedGoogle Scholar
  14. 14.
    Roetto A, Totaro A, Piperno A, et al. New mutations inactivating transferrin receptor 2 in hemochromatosis type 3.Blood. 2001;97: 2555–2560.CrossRefPubMedGoogle Scholar
  15. 15.
    Camaschella C, Roetto A, Cali A, et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22.Nat Genet.2000;25:14–15.CrossRefPubMedGoogle Scholar
  16. 16.
    West AP, Bennett M, Sellers VM, Andrews NC, Enns CA, Bjorkman PJ. Comparison of the interactions of transferrin receptor and transferrin receptor 2 with transferrin and the hereditary hemochromatosis protein HFE.J Biol Chem. 2000; 276:38135–38138.CrossRefGoogle Scholar
  17. 17.
    Melefors O, Hentze MW. Iron regulatory factor: the conductor of cellular iron regulation.Blood Rev. 1993;7:251–258.CrossRefPubMedGoogle Scholar
  18. 18.
    Casey JL, Hentze MW, Koeller DM, et al. Iron-responsive elements: regulatory RNA sequences that control mRNA levels and translation.Science. 1988;240:924–928.CrossRefPubMedGoogle Scholar
  19. 19.
    Mullner EW, Neupert B, Kuhn LC. A specific mRNA binding factor regulates the iron-dependent stability of cytoplasmic transferrin receptor mRNA.Cell. 1989;58:373–382.CrossRefPubMedGoogle Scholar
  20. 20.
    Ponka P. Tissue-specific regulation of iron metabolism and heme synthesis: distinct control mechanisms in erythroid cells.Blood. 1997;89:1–25.PubMedGoogle Scholar
  21. 21.
    Pantopoulos K, Hentze MW. Rapid responses to oxidative stress mediated by iron regulatory protein.EMBO J. 1995;14:2917–2924.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Weiss G, Houston T, Kastner S, Johrer K, Grunewald K, Brock JH. Regulation of cellular iron metabolism by erythropoietin: activation of iron-regulatory protein and upregulation of transferrin receptor expression in erythroid cells.Blood. 1997;89:680–687.PubMedGoogle Scholar
  23. 23.
    Hirayama M, Kohgo Y, Kondo H, et al. Regulation of iron metabolism in HepG2 cells: a possible role for cytokine in the hepatic deposition of iron.Hepatology. 1993;18:874–870.CrossRefPubMedGoogle Scholar
  24. 24.
    Toth I, Yuan L, Rogers JT, Boyce H, Bridges KR. Hypoxia alters iron-regulatory protein-1 binding capacity and modulates cellular iron homeostasis in human hepatoma and erythroleukemia cells.J Biol Chem. 1999;274:4467–4473.CrossRefPubMedGoogle Scholar
  25. 25.
    Lok CN, Ponka P. Identification of an erythroid active element in the transferrin receptor gene.J Biol Chem. 2000;275:24185–24190.CrossRefPubMedGoogle Scholar
  26. 26.
    Flemming RE, Migas MC, Holden CC, et al.Transferrin receptor 2: continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis.Proc Natl Acad Sci U S A.2000;97:2214–2219.CrossRefGoogle Scholar
  27. 27.
    Kawabata H, Nakamaki T, Ikonomi P, Smith RD, Germain RS, Koefler HP. Expression of transferrin receptor 2 in normal and neoplastic cells.Blood. 2001;98:2714–2719.CrossRefPubMedGoogle Scholar
  28. 28.
    Lebron JA, Bennett MJ, Vaughn DE, et al. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor.Cell. 1998;93:111–123.CrossRefPubMedGoogle Scholar
  29. 29.
    Bennett MJ, Lebron JA, Bjorkman PJ. Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor.Nature. 2000;403:46–53.CrossRefPubMedGoogle Scholar
  30. 30.
    Feder JN, Penny DM, Irrinki A, et al. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding.Proc Natl Acad Sci U S A. 1998;95: 1472–1477.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Ikuta K, Fujimoto Y, Suzuki Y, et al. Overexpression of hemochromatosis protein, HFE, alters transferrin recycling process in human hepatoma cells.Biochim Biophys Acta. 2000;1496:221–231.CrossRefPubMedGoogle Scholar
  32. 32.
    West AP Jr, Giannetti AM, Herr AB, et al. Mutation analysis of the transferrin receptor reveals overlapping HFE and transferrin binding sites.J Mol Biol. 2001;313:385–397.CrossRefPubMedGoogle Scholar
  33. 33.
    Canonne-Hergaux F, Zhang AS, Ponka P, Gros P. Characterization of the iron transporter DMT1 (NRAMP2/DCT1) 1 in red blood cells of normal and anemic mk/mk mice.Blood. 2001;98:3823–3830.CrossRefPubMedGoogle Scholar
  34. 34.
    Kohgo Y, Niitsu Y, Nishisato T, et al. Externalization of transferring receptor in established cell lines.Cell Biol Int Rep. 1987;11:871–879.CrossRefPubMedGoogle Scholar
  35. 35.
    Rutledge EA, Green FA, Enns CA. Generation of the soluble transferrin receptor requires cycling through an endosomal compartment.J Biol Chem. 1994;269:31864–31868.PubMedGoogle Scholar
  36. 36.
    Bayness RD, Shih YJ, Hudson BG, Cook JD. Production of the serum form of the transferrin receptor by a cell membrane-associated serine protease.Proc Soc Exp Biol Med. 1993;204:65–69.CrossRefGoogle Scholar
  37. 37.
    Kato J, Kobune M, Kohgo Y, et al. Ratio of transferrin (TF) to Tf-receptor complex in circulation differs depending on Tf iron saturation.Clin Chem. 2002;48:181–183.PubMedGoogle Scholar
  38. 38.
    Kohgo Y, Niitsu Y, Kondo H, et al. Serum transferrin receptor as a new index of erythropoiesis.Blood. 1987;70:1955–1958.PubMedGoogle Scholar
  39. 39.
    Cook JD, Skikne BS, Baynes RD. Serum transferrin receptor.Annu Rev Med. 1993;44:63–74.CrossRefPubMedGoogle Scholar
  40. 40.
    Skikne BS. Circulating transferrin receptor assay: coming of age.Clin Chem. 1998;44:7–9.PubMedGoogle Scholar
  41. 41.
    Skikne BS, Flowers CH, Cook JD. Serum transferrin receptor: a quantitative measure of tissue iron deficiency.Blood. 1990;75: 1870–1876.PubMedGoogle Scholar
  42. 42.
    Huebers HA, Beguin Y, Pootrakul P, Einspahr D, Finch CA. Intact transferrin receptors in human plasma and their relation to erythropoiesis.Blood. 1990;75:102–107.PubMedGoogle Scholar
  43. 43.
    R’zik S, Beguin Y. Serum soluble transferrin receptor concentration is an accurate estimate of the mass of tissue receptors.Exp Hematol. 2001;29:677–685.CrossRefPubMedGoogle Scholar
  44. 44.
    Choi JW, Pai SH, Im MW, Kim SK. Serum transferrin receptor concentrations with age.Clin Chem. 1999;45:1562–1563.PubMedGoogle Scholar
  45. 45.
    Cooper MJ, Zlotkin SH. Day-to-day variation of transferrin receptor and ferritin in healthy men and women.Am J Clin Nutr. 1996; 64:738–742.CrossRefPubMedGoogle Scholar
  46. 46.
    Virtanen MA, Viinikka LU, Virtanen MK, et al. Higher concentrations of serum transferrin receptor in children than in adults.Am J Clin Nutr. 1999;69:256–260.PubMedGoogle Scholar
  47. 47.
    Kohgo Y, Niitsu Y, Nishisato T, et al. Immunoreactive transferrin receptor in sera of pregnant women.Placenta. 1988;9:523–531.CrossRefPubMedGoogle Scholar
  48. 48.
    Choi JW, Pai SH. Change in erythropoiesis with gestational age during pregnancy.Ann Hematol. 2001;80:26–31.CrossRefPubMedGoogle Scholar
  49. 49.
    Akesson A, Bjellerup P, Ferglund M, Bremme K, Vahter M. Serum transferrin receptor: a specific marker of iron deficiency in pregnancy.Am J Clin Nutr. 1998;68:1241–1246.CrossRefPubMedGoogle Scholar
  50. 50.
    Zhu YI, Haas JD. Response of serum transferrin receptor to iron supplementation in iron-depleted nonanemic women.Am J Clin Nutr. 1998;67:271–275.CrossRefPubMedGoogle Scholar
  51. 51.
    Khumalo H, Gomo ZAR, Moyo VM, et al. Serum transferrin receptors are decreased in the presence of iron overload.Clin Chem. 1998;44:40–44.PubMedGoogle Scholar
  52. 52.
    Gimferrer E, Ubeda J, Royo MT, et al. Serum transferrin receptor levels in different stages of iron deficiency.Blood. 1997;90: 1332–1334.PubMedGoogle Scholar
  53. 53.
    Suominen P, Punnonen K, Rajamaki A, Irjata K. Serum transferrin receptor and transferrin receptor-ferritin index identify healthy subjects with subclinical iron deficits.Blood. 1998;92:2934–2939.PubMedGoogle Scholar
  54. 54.
    Kohgo Y, Niitsu Y, Nishisato T, et al. Quantitation and characterization of serum transferrin receptor in patients with anemias and polycythemias.Jpn J Med. 1988;27:64–70.CrossRefPubMedGoogle Scholar
  55. 55.
    Verhoer H, West CE, Ndeto P, Burema J, Beguin Y, Kok FJ. Serum transferrin receptor concentration indicates increased erythropoiesis in Kenyan children with asymptomatic malaria.Am J Clin Nutr. 2001;74:767–775.CrossRefGoogle Scholar
  56. 56.
    Bessho M, Hirashima K,Asano S, et al. Treatment of the anemia of aplastic anemia patients with recombinant human erythropoietin in combination with granulocyte colony-stimulating factor: a multicenter randomized controlled study. Muticenter Study Group.Eur J Haematol. 1997;58:265–272.CrossRefPubMedGoogle Scholar
  57. 57.
    Testa U, Rutella S, Martucci R, et al. Autologous stem cell transplantation: evaluation of erythropoietic reconstitution by highly fluorescent reticulocyte counts, erythropoietin, soluble transferrin receptors, ferritin, TIBC and iron dosages.Br J Haematol. 1997;96: 762–775.CrossRefPubMedGoogle Scholar
  58. 58.
    Beguin Y. Prediction of response to optimize outcome of treatment with erythropoietin.Semin Oncol. 1998;25(suppl 7):27–34.PubMedGoogle Scholar
  59. 59.
    Chen C-H, Cheng C-H, Cheng T-C, Shu K-H, Wu M-N, Lian J-D. Serum transferrin receptor is a good index of erythropoietin treatment in ESRD.Acta Nephrol. 1998;12:6–11.Google Scholar
  60. 60.
    Beguin Y, Loo M, R’Zik S, et al. prediction of response to recombinant human erythropoietin in patients with the anemia of renal failure by serum transferrin receptor and fibrinogen.Blood. 1993; 82:2010–2016.PubMedGoogle Scholar
  61. 61.
    Ahluwalia N, Skikne BS, Savin V, Chonko A. Markers of masked iron deficiency and effectiveness of EPO therapy in chronic renal failure.Am J Kidney Dis. 1997;30:532–541.CrossRefPubMedGoogle Scholar
  62. 62.
    Song JS, Park W, Bae SK, et al. The usefulness of serum transferrin receptor (sTfR) and ferritin in anemic patients with rheumatoid arthritis (RA) compared with bone marrow storage iron and other tests for anemia.Rheumatol Int. 2001;21:24–29.CrossRefPubMedGoogle Scholar
  63. 63.
    Baumann Kurer S, Seifert B, Michel B, Ruegg R, Fehr J. Prediction of iron deficiency in chronic inflammatory rheumatic disease anaemia.Br J Haematol. 1995;91:820–826.CrossRefGoogle Scholar
  64. 64.
    Punnonen K, Irjala K, Rajamaki. Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency.Blood. 1997;89:1052–1057.PubMedGoogle Scholar
  65. 65.
    Malope BI, MacPhail P, Alberts M, Hiss DC. The ratio of serum transferrin receptor and serum ferritin in the diagnosis of iron status.Br J Haematol. 2001;115:84–89.CrossRefPubMedGoogle Scholar
  66. 66.
    van Tellingen A, Kuenen JC, de Kieviet W, van Tinteren H, Kooi ML, Vasmel WL. Iron deficiency anemia in hospitalized patients: value of various laboratory parameters: differentiation between IDA and ACD.Neth J Med. 2001;59:270–279.CrossRefPubMedGoogle Scholar
  67. 67.
    Means RT Jr. Advances in the anemia of chronic disease.Int J Hematol. 1999;70:7–12.PubMedGoogle Scholar
  68. 68.
    Cartwright GE. The anemia of chronic disorders.Semin Hematol. 1966;3:351–368.PubMedGoogle Scholar
  69. 69.
    Alvarez-Hernandez X, Liceaga J, McKay IC, Brock JH. Induction of hypoferremia and modulation of macrophage iron metabolism by tumor necrosis factor.Lab Invest. 1986;61: 319–322.Google Scholar
  70. 70.
    Rogers JT, Bridges KR, Durmowicz GP, Glass J, Auron PE, Munro HN. Translational control during the acute phase response: ferritin synthesis in response to interleukin 1.J Biol Chem. 1990;265: 14572–14578.PubMedGoogle Scholar
  71. 71.
    Kobune M, Kohgo Y, Kato J, Miyazaki E, Niitsu Y. Interleukin-6 enhances hepatic transferrin uptake and ferritin expression in rats.Hepatology. 1994;19:1468–1475.CrossRefPubMedGoogle Scholar
  72. 72.
    Weiss G, Bogdan C, Hentze MW. Pathways for the regulation of macrophage iron metabolism by the anti-inflammatory cytokines IL-4 and IL-13.J Immunol. 1997;158:420–425.PubMedGoogle Scholar
  73. 73.
    Hentze MW, Kuhn LC. Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress.Proc Natl Acad Sci U S A. 1996; 93:8175–8182.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Suominen P, Punnonen K, Rajamaki A, Irjala K. Evaluation of new immunoenzymometric assay for measuring soluble transferrin receptor to detect iron deficiency in anemic patients.Clin Chem. 1997;43:1641–1646.PubMedGoogle Scholar
  75. 75.
    Coenen JL, van Dieijen-Visser MP, van Pelt J, et al. Measurements of serum ferritin used to predict concentrations of iron in bone marrow in anemia of chronic disease.Clin Chem. 1991;37:560–563.PubMedGoogle Scholar
  76. 76.
    Torimoto Y, Kohgo Y. Transferrin receptor in erythropoiesis [in Japanese].Rinsho Ketsueki. 2000;41:554–558.PubMedGoogle Scholar
  77. 77.
    Kohgo Y. Disorders of iron metabolism involving erythropoiesis: molecular mechanism of gut-liver-bone marrow axis [in Japanese].Rinsho Ketsueki. 2001;42:397–402.PubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2002

Authors and Affiliations

  1. 1.Third Department of Internal MedicineAsahikawa Medical CollegeAsahikawa, HokkaidoJapan
  2. 2.Fourth Department of Internal MedicineSapporo Medical UniversitySapporoJapan

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