Lactoferrin pp 99-109 | Cite as

The Monocytic Receptor for Lactoferrin and its Involvement in Lactoferrin-Mediated Iron Transport

  • Henrik S. Birgens
Part of the Advances in, Experimental Medicine and Biology book series (AEMB, volume 357)


Several studies suggest biological functions of the iron-binding neutrophilic glycoprotein lactoferrin that imply an initial interaction with cells from the monocyte/macrophage family. Among these, an important role of lactoferrin as responsible for the inflammatory-induced blood hyposideremia and accumulation of iron in the monocyte/macrophage system has been suggested mainly based on experiments in rodents.

In a series of experiments we have examined the binding of human lactoferrin to human monocytes. We have demonstrated the presence of a receptor binding including a high-affinity component and a low-affinity component. The affinity of the binding is compatible with a biological significance of this receptor (KD is about 10-8 M, and the number of receptors about 106 per cell). More than 90 % of the lactoferrin will dissociate from the cell. The binding is not truly reversible since lactoferrin will lose its receptor-binding property after dissociation from the cell. The only observed change in the molecule is a small decrease in isoelectric point from 8.9 to 8.8.

Lactoferrin is able to translocate at least 50 % of its bound iron to intracellular ferritin in monocytes. These findings are compatible with the idea that lactoferrin might be involved in the pathogenesis of the disturbances in iron metabolism observed during inflammation.


Human Monocyte Human Lactoferrin Lactoferrin Receptor Lactoferrin Concentration Intracellular Ferritin 
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  1. 1.
    Sørensen M., Sørensen SPL, (1939) The proteins in whey. CR Trav Lab Carlsberg 23: 55–99.Google Scholar
  2. 2.
    Aisen P, Listowsky I (1980) Iron transport and storage proteins. Ann Rev Biochem 49:357–393.PubMedCrossRefGoogle Scholar
  3. 3.
    Metz-Boutigue MH, Joliés J, Mazurier J, Schoentgen F, Legrand D, Spik, G, Montreuil J, Joliés P (1984) Human lactotransferrin: amino acid sequence and structural comparisons with other transferrins. EurJ Biochem 145:659–675.CrossRefGoogle Scholar
  4. 4.
    Matzsumoto A, Yoshima H, Takasaki S, Kobata A (1982) Structural study of the sugar chains of human lactoferrin: Finding of four novel complex-type asparagine-linked sugar chains. J Biochem 91:143–155.Google Scholar
  5. 5.
    Baker EN, Anderson BF, Baker HM, Haridas M., Jameson GB, Noms GE, Rumball SV, Smith CA (1991) Structure, function and flexibility of human lactoferrin. Int J Biol. Macromol 13: 122–129.CrossRefGoogle Scholar
  6. 6.
    Powell MJ, Ogden JE (1990) Nucleotide sequence of human lactoferrin cDNA. Nucleic Acids Research 18: 4013.PubMedCrossRefGoogle Scholar
  7. 7.
    Masson PL, Heremans JF. (1966) Studies on lactoferrin, the iron-binding protein of secretions. Prot Biol. Fluids 14: 115–124.Google Scholar
  8. 8.
    Van Snick JL, Masson PL, Heremans JF. (1974) The involvement of lactoferrin in the hyposideremia of acute inflammation. J Exp Med 140: 1068–1084.PubMedCrossRefGoogle Scholar
  9. 9.
    Van Snick JL, Masson PL. (1976) The binding of lactoferrin to mouse peritoneal cells. J Exp Med 144: 1568–1580.PubMedCrossRefGoogle Scholar
  10. 10.
    Van Snick JL, Markowetz B, Masson PL.(1977) The ingestion and digestion of human lactoferrin by mouse peritoneal macrophages and transfer of its iron into ferritin. J Exp Med 146:817–827.PubMedCrossRefGoogle Scholar
  11. 11.
    Broxmeyer HE, Smithyman A, Eger RR, Meyers PA, DeSousa M.(1978) Identification of lactoferrin as the granulocyte-derived inhibitor of colony-stimulating activity production. J Exp Med 148:1052–1067.PubMedCrossRefGoogle Scholar
  12. 12.
    Zucalli JR, Broxmeyer HE, Morse C.(1989) Lactoferrin decreases monocyte-induced fibroblast production of myeloid-stimulating activity by suppressing monocyte release of interleukin-1. Blood 74:1531–1536.Google Scholar
  13. 13.
    Duncan RL, McArthur WP. (1981) Lactoferrin-mediated modulation of mononuclear cell activities: I. Suppression of the murine in vitro primary antibody response. Cell Immunol 63: 308–320.PubMedCrossRefGoogle Scholar
  14. 14.
    Nishiya K, Horwitz DA.(1982) Contrasting effects of lactoferrin on human lymphocyte and monocyte natural killer activity and antibody-dependent cell-mediated cytotoxicity. J Immunol 129:2519–2523.PubMedGoogle Scholar
  15. 15.
    Lima MF, Kierszenbaum F. (1985) Lactoferrin effects on phagocytic cell function. I. Increased uptake and killing of an intracellular parasite by murine macrophages and human monocytes. J Immunol 134: 4176–4183.PubMedGoogle Scholar
  16. 16.
    Birgens HS.(1985) Lactoferrin measured by an ELISA technique: Evidence that plasma lactoferrin is an indicator of neutrophil turnover and bone marrow activity in acute leukaemia. Scand J Haematol 34:326–331.PubMedCrossRefGoogle Scholar
  17. 17.
    Thorell JI, Johansson BG.(1971) Enzymatic iodination of polypeptides with 125I to high specific activity. Biochim Biophys Acta 251:363–369.PubMedCrossRefGoogle Scholar
  18. 18.
    Masson PL, Heremans JF. (1968) Metal-combining properties of human lactoferrin (red milk protein). I The involvement of bicarbonate in the reaction. Europ J Biochem 6: 579–584.PubMedCrossRefGoogle Scholar
  19. 19.
    Birgens HS, Hansen NE, Karle H, Kristensen LØ. (1983). Receptor binding of lactoferrin by human monocytes. Brit J Haematol 54: 383–391.CrossRefGoogle Scholar
  20. 20.
    Britigan BE, Serody JS, Hayek MB, Charniga LM, Cohen MS.(1991) Uptake of human lactoferrin by mononuclear phagocytes inhibits their ability to form hydroxyl radical and protects them from membrane autoperoxidation. J Immunol 147:4271–4277.PubMedGoogle Scholar
  21. 21.
    Bennett RM, Davis J (1981) Lactoferrin binding to human peripheral blood cells: An interaction with Benriched populations of lymphocytes and a subpopulation of adherent mononuclear cells. J Immunol 127:1211–1216.PubMedGoogle Scholar
  22. 22.
    Campbell EJ.(1982) Human leukocyte elastase, cathepsin G, and lactoferrin: Family of neutrophil granule glycoproteins that bind to an alveolar macrophage receptor. Proc Natl Acad Sci 79:6941–6945.PubMedCrossRefGoogle Scholar
  23. 23.
    Bartal L, Padeh S, Passwell JH. (1987) Lactoferrin inhibits prostaglandin E2 secretion by breast milk macrophages. Pediatr Res 21: 54–57.PubMedCrossRefGoogle Scholar
  24. 24.
    Markowetz B, Van Snick JL, Masson PL.(1979) Binding and ingestion of human lactoferrin by mouse alveolar macrophages. Thorax 34:209–212.PubMedCrossRefGoogle Scholar
  25. 25.
    Birgens HS, Karle K, Hansen NE, Kristensen L0.(1984) Lactoferrin binding to peripheral human leukocytes. Prot Biol Fluids 31:145–148.Google Scholar
  26. 26.
    Schaumburg BP, Bojesen E.(1968) Specificity and thermodynamic properties of the corticosteroid binding to a receptor of rat thymocytes in vitro. Biochim Biophys Acta 170:172–188.PubMedCrossRefGoogle Scholar
  27. 27.
    Rodbard D, Munson PJ, Thakur AK. (1980) Quantitative characterization of hormone receptors. Cancer 46:2907–2918.PubMedCrossRefGoogle Scholar
  28. 28.
    Scatchard G.(1949) The attractions of proteins for small molecules and ions. Ann NY Acad Sci 51:660–672.CrossRefGoogle Scholar
  29. 29.
    Birgens HS, Karle H, Hansen NE, Kristensen LØ.(1984) Lactoferrin receptors in normal and leukaemic human blood cells. Scand J Haematol 33:275–280.PubMedCrossRefGoogle Scholar
  30. 30.
    DeMeyts P, Raffaele Bianco A, Roth J.(1976) Site-site interactions among insulin receptors. J Biol Chem 251:1877–1888.PubMedGoogle Scholar
  31. 31.
    Birgens HS, Kristensen LØ.(1990) Impaired receptor-binding and decrease in isoelectric point of lactoferrin after binding and uptake into human monocytes. Europ J Haematol 45:31–35.CrossRefGoogle Scholar
  32. 32.
    Estevenon JP, Figarella C.(1983) A non-competitive enzyme immunoassay of human lactoferrin in biological fluids. Clin Chim Acta 129:311–318.PubMedCrossRefGoogle Scholar
  33. 33.
    Adayemi EO, Hodgson, HJF.(1988) Augmented release of human leukocyte lactoferrin (and elastase) during coagulation. J Clin Lab Immunol 27:1–4.Google Scholar
  34. 34.
    Hansen NE, Karle H, Andersen V, Malmquist J, Hoff GE. (1976). Neutrophilic granulocytes in acute bacterial infection. Sequential studies on lysozyme, myeloperoxidase and lactoferrin. Clin Exp Med 26: 463–468.Google Scholar
  35. 35.
    Baynes R, Bezwoda W, Bothwell T, Khan Q, Mansoor N.(1986) The non-immune inflammatory response: serial changes in plasma iron, iron-binding capacity, lactoferrin, ferritin and C-reactive protein. Scand J Lab Invest. 46:695–704.CrossRefGoogle Scholar
  36. 36.
    Nuijens JH, Abbink JJ, Wachtfogel YT, Colman RW, Eerenberg AJM, Dors D, Kamp AJM, Strack van Schijndel RJM, Thijs LG, Hack CE.(1992) Plasma elastase, alfa1-antitrypsin and lactoferrin in sepsis: Evidence for neutrophils as mediators in fatal sepsis. J Lab Clin Med 119:159–168.PubMedGoogle Scholar
  37. 37.
    Wolach B, Coates TD, Hugli TE, Baehner RL, Boxer LA.(1984) Plasma lactoferrin reflects granulocyte activation via complement in burn patients. J Lab Clin Med 103:284–293.PubMedGoogle Scholar
  38. 38.
    Lash JA, Coates TD, Lafuze J, Baehner RL, Boxer LA.(1983) Plasma lactoferrin reflects granulocyte activation in vivo. Blood 61:885–888.PubMedGoogle Scholar
  39. 39.
    Bennett RM, Skosey JL. (1977). Lactoferrin and lysozyme levels in synovial fluid. Differential indices of articular inflammation and degradation. Arthrites and Rheumatism 20: 84–90.CrossRefGoogle Scholar
  40. 40.
    Mazurier J, Metz-Boutigue MH, Joliés J, Spik G, Montreuil J, Joliés P. (1983) Human lactotransferrin: Molecular, functional and evolutionary comparisons with human transferrin and hen ovotransferrin. Experientia 135-141.Google Scholar
  41. 41.
    Moguilevsky N, Retegui LA, Courtoy PJ, Castracane CE, Masson PL. (1984) Uptake of lactoferrin by the liver. III. Critical role of the protein moiety. Lab Invest 50: 335–340.PubMedGoogle Scholar
  42. 42.
    Birgens HS, Kristensen LØ, Borregaard N, Karle H, Hansen NE.(1988) Lactoferrin-mediated transfer of iron to intracellular ferritin in human monocytes. Europ J Haematol 41:52–57.CrossRefGoogle Scholar
  43. 43.
    Moguilevsky N. Masson PL, Courtoy PJ.(1987) Lactoferrin uptake and iron processing into macrophages: a study in familial haemochromatosis. Brit J Haematol 66:129–136.Google Scholar
  44. 44.
    Hansen NE, Malmquist J, Thorell J.(1975) Plasma myeloperoxidase and lactoferrin measured by radioimmunoassay: Relations to neutrophil kinetics. Acta Med Scand 198:437–443.PubMedCrossRefGoogle Scholar
  45. 45.
    Moguilevsky N, Retegui LA, Masson PL. (1985) Comparisons of human lactoferrins from milk and neutrophilic leukocytes. Relative molecular mass, isoelectric point, iron-binding properties and uptake by the liver. Biochem J 229: 353–359.PubMedGoogle Scholar
  46. 46.
    Furmanski P, Li Z-.(1990) Multiple forms of lactoferrin in normal and leukemic human granulocytes. Exp Hematol 18:932–935.PubMedGoogle Scholar
  47. 47.
    Steinmann G, Broxmeyer HE, DeHarven E, Moore MAS.(1982) Immuno-electron microscopic tracing of lactoferrin, a regulator of myelopoiesis, into a subpopulation of human peripheral blood monocytes. Brit J Haematol 50:75–84.CrossRefGoogle Scholar
  48. 48.
    Aisen P, Leibman A. (1972) Lactoferrin and transferrin: a comparative study. Biochim Biophys Acta 257:314–323.PubMedCrossRefGoogle Scholar
  49. 49.
    Lee GR.(1983) The anemia of chronic disease. Sem Hematol 20:61–80.Google Scholar
  50. 50.
    Quastel MR, Ross JF.(1966) The effect of acute inflammation on the utilization and distribution of trans-ferrin-bound and erythrocyte radioiron. Blood 28:738–757.PubMedGoogle Scholar
  51. 51.
    Fillet G, Cook JD, Finch CA. (1974) Storage iron kinetics VII. A Biological model for reticuloendothelial iron transport. J Clin Invest 53: 1527–1533.CrossRefGoogle Scholar
  52. 52.
    Goldblum SE, Cohen D, Jay M., McClain CJ. (1987) Interleukin 1-induced depression of iron and zinc: role of granulocytes and lactoferrin. Am J Physiol 252: E27–32.PubMedGoogle Scholar
  53. 53.
    Kampschmidt RF, Upchurch.(1969) Lowering of plasma iron concentration in the rat with leukocytic extracts. Am J Physiol 216:1287–1291.PubMedGoogle Scholar
  54. 54.
    Bertini R, Wang JM, Mengozzi M., Willems J, Joniau M., Van Damme J, Ghezzi P.(1991) Effects of chlorpromazine on PMN-mediated activities in-vivo and in-vitro. Immunology 72:138–143.PubMedGoogle Scholar
  55. 55.
    Klempner MS, Dinarello CA, Gallin JI.(1978) Human leukocytic pyrogen induces release of specific granule contents from human neutrophils. J Clin Invest 61:1330–1336.PubMedCrossRefGoogle Scholar
  56. 56.
    Gutteberg TJ, Røkke O, Jørgensen T, Andersen O.(1988) Lactoferrin as an indicator of septicemia and endotoxemia in pigs. Scand J Infect Dis 20:659–666.PubMedCrossRefGoogle Scholar
  57. 57.
    Koivuranta-Vaara P, Banda D, Goldstein IM.(1987) Bacterial lipopolysaccharide-induced release of lactoferrin from human polymorphonuclear leukocytes: Role of monocyte-derived tumor necrosis factor alpha. Infect Immun 55:2956–2961.PubMedGoogle Scholar
  58. 58.
    Leffell MS, Spitznagel JK.(1975) Fate of human lactoferrin and myeloperoxidase in phagocytizing human neutrophils: Effects of immunoglobulin G subclasses and immune complexes coated with latex beads. Infect Immun 12:813–820.PubMedGoogle Scholar
  59. 59.
    Prieels JP, Pizzo SV, Glasgow LR, Paulson JC, Hill RL.(1978) Hepatic receptor that specifically binds oligosaccharides containing fucosyl alphal3 N-acethylglucosamine linkages. Proc Natl Acad Sci 75:2215–2219.PubMedCrossRefGoogle Scholar
  60. 60.
    Bennett RM, Kokocinski T (1979) Lactoferrin turnover in man. Clin Sci 57:453–460.PubMedGoogle Scholar
  61. 61.
    Courtoy PJ, Moguilevsky N, Retegui LA, Castracane CE, Masson PL. (1984) Uptake of lactoferrin by the liver. II. Endocytosis by sinusoidal cells. Lab Invest 50: 329–334.PubMedGoogle Scholar
  62. 62.
    McAbee DD, Esbensen K.(1991) Binding and endocytosis of apo-and holo-lactoferrin by isolated rat hepatocytes. J Biol Chem 266:23624–23631.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Henrik S. Birgens
    • 1
    • 2
  1. 1.Department of Hematology L Herlev HospitalUniversity of CopenhagenHerlevDenmark
  2. 2.Department of Hematology LHerlev HospitalHerlevDenmark

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