Lactoferrin — an endogenous regulator of the protective functions of the organism

Cover Page
Open Access Open Access
Restricted Access Subscription Access


Lactoferrin — multifunctional glycoprotein of the transferrin family with a molecular mass of about 80 kDa. The review presents data on the physicochemical properties and localization of the protein, on antimicrobial properties, antitumor and anti-inflammatory effects, participation in neuroendocrinoimmune interactions, and on possible mechanisms for the realization of its functional manifestations.

Galina M. Aleshina

Institute of Experimental Medicine

Author for correspondence.
ORCID iD: 0000-0003-2886-7389

Russian Federation, Saint Petersburg

канд. биол. наук, доцент, ведущий научный сотрудник

  1. Sorensen M, Sorensen JPL. The proteins in whey. C R Trav Lab Carlsberg. 1939;23(1):55-99.
  2. Groves ML. The Isolation of a Red Protein from Milk2. J Amer Chem Soc. 1960;82(13):3345-3350.
  3. Johanson B. Isolation of an iron-containing red protein from human milk. Acta Chem Scand. 1960;14(2):510-512.
  4. Masson PL, Heremans JF. Lactoferrin in milk from different species. Comp Biochem Physiol B. 1971;39(1):119-129.
  5. Masson PL. La lactoferrine. Proteine des secretions externes et des leucocyte neutrophiles. Brussel: Aracia; 1970. 232 p.
  6. Baer A, Oroz M, Blanc B. Isolation and partial characterization of ovine lactoferrin. Experientia. 1979;35(12):1554-1555.
  7. Oram JD, Reiter B. Inhibition of bacteria by lactoferrin and other iron-chelating agents. Biochim Biophys Acta Gen Subj. 1968;170(2):351-365.
  8. Roberts TK, Boursnell JC. The Isolation and Characterization of Lactoferrin from Sow Milk and Boar Seminal Plasma. Reproduction. 1975;42(3):579-582.
  9. Jollès J, Donda A, Amiguet P, Joliès P. Mare lactotransferrin: purification, analysis and N-terminal sequence determination. FEBS Lett. 1984;176(1):185-188.
  10. Kinkade JM, Kendall Miller WW, Segars FM. Isolation and characterization of murine lactoferrin. Biochim Biophys Acta Proteins Struct. 1976;446(2):407-418.
  11. Берлов М.Н., Кораблева Е.С., Андреева Ю.В., и др. Лактоферрин из нейтрофилов собаки: выделение, физико-химические и антимикробные свойства // Биохимия. – 2007. – Т. 72. – № 4. – С. 551–559. [Berlov MN, Korableva ES, Andreeva YV, et al. Lactoferrin from canine neutrophils: Isolation and physicochemical and antimicrobial properties. Biokhimiia. 2007;72(4):551-559. (In Russ.)]
  12. Biserte G, Havez R, Cuvelier R. The Glycoproteins of Bronchial Secretions. Expos Annu Biochim Med. 1963;24:85-120.
  13. Masson PL, Heremans JF, Prignot JJ, Wauters G. Immunohistochemical localization and bacteriostatic properties of an iron-binding protein from bronchial mucus. Thorax. 1966;21(6):538-544.
  14. Masson PL. Lactoferrin, an Iron-Binbing Protein Ni Neutrophilic Leukocytes. J Exp Med. 1969;130(3):643-658.
  15. Baggiolini M. Association of Lactoferrin with Specific Granules in Rabbit Heterophil Leukocytes. J Exp Med. 1970;131(3):559-570.
  16. Bretz U. Biochemical and Morphological Characterization of Azurophil and Specific Granules of Human Neutrophilic Polymorphonuclear Leukocytes. J Cell Biol. 1974;63(1):251-269.
  17. Anderson BF, Baker HM, Norris GE, et al. Structure of human lactoferrin: Crystallographic structure analysis and refinement at 2·8 Å resolution. J Mol Biol. 1989;209(4):711-734.
  18. Ward PP, Zhou X, Conneely OM. Cooperative Interactions between the Amino- and Carboxyl-terminal Lobes Contribute to the Unique Iron-binding Stability of Lactoferrin. J Biol Chem. 1996;271(22):12790-12794.
  19. Baker EN, Baker HM. Molecular structure, binding properties and dynamics of lactoferrin. Cell Mol Life Sci. 2005;62(22):2531-2539.
  20. Ainscough EW, Brodie AM, Plowman JE. The chromium, manganese, cobalt and copper complexes of human lactoferrin. Inorganica Chim Acta. 1979;33:149-153.
  21. Hansen NE, Malmquist J, Thorell J. Plasma myeloperoxidase and lactoferrin measured by radioimmunoassay: relations to neutrophil kinetics. Acta Med Scand. 1975;198(6):437-443.
  22. Bullen JJ, Rogers HJ, Leigh L. Iron-binding proteins in milk and resistance to Escherichia coli infection in infants. Br Med J. 1972;1(5792):69-75.
  23. Weinberg ED. The Development of Awareness of Iron-withholding Defense. Perspect Biol. Med. 1993;36(2):215-221.
  24. Singh PK, Parsek MR, Greenberg EP, Welsh MJ. A component of innate immunity prevents bacterial biofilm development. Nature. 2002;417(6888):552-555.
  25. Bellamy W, Takase M, Wakabayashi H, et al. Antibacterial spectrum of lactoferricin B, a potent bactericidal peptide derived from the N-terminal region of bovine lactoferrin. J Appl Bacteriol. 1992;73(6):472-479.
  26. Wakabayashi H, Abe S, Okutomi T, et al. Cooperative Anti-CandidaEffects of Lactoferrin or Its Peptides in Combination with Azole Antifungal Agents. Microbiology and Immunology. 1996;40(11):821-825.
  27. van Snick JL. The Involvement of Lactoferrin in the Hyposideremia of Acute Inflammation. J Exp Med. 1974;140(4):1068-1084.
  28. Николаев А.А., Аншакова Н.И. Иммунохимическая и физико-химическая характеристика лактоферрина биологических жидкостей человека // Вопросы медицинской химии. – 1985. – Т. 31. – № 3. – С. 128–132. [Nikolaev AA, Anshakova NI. Immunokhimicheskaya i fiziko-khimicheskaya kharakteristika laktoferrina biologicheskikh zhidkostey cheloveka. Vopr Med Khim. 1985;45(3):128-132. (In Russ.)]
  29. Nagasawa T, Kiyosawa I, Kuwahara K. Amounts of Lactoferrin in Human Colostrum and Milk. J Dairy Sci. 1972;55(12):1651-1659.
  30. Embleton ND, Berrington JE, McGuire W, et al. Lactoferrin: Antimicrobial activity and therapeutic potential. Semin Fetal Neonatal Med. 2013;18(3):143-149.
  31. Maacks S, Yuan H-Z, Wood WG. Development and evaluation of luminescence-based sandwich assay for plasma lactoferrin as a marker for sepsis and bacterial infections in paediatric medicine. J Biolumin Chemilumin. 1989;3(4):221-226.
  32. Ботерашвили Н.М., Алешина Г.М., Сорокина М.Н., и др. Миелопероксидаза и лактоферрин в сыворотке крови и ликворе детей больных менингитом. // Медицинская иммунология. – 2002. – Т. 4. – № 4-5. – С. 565–572. [Boterashvili NM, Aleshina GM, Sorokina MN, et al. Neutrophil Proteins in the Serum and the Cerebrospinal Fluid of Children with Meningitis. Meditsinskaia immunologiia. 2002;4(4-5):565-572. (In Russ.)]
  33. Суркова Е.А., Булгакова Т.В., Сологуб Т.С., и др. Миелопероксидаза и лактоферрин у больных муковисцедозом // Медицинская иммунология. – 2004. – Т. 6. – № 1-1. – С. 67–74. [Surkova EA, Bulgakova TV, Sologub TS, et al. Myeloperoxidase and lactoferrin from cystic fibrosis patients. Meditsinskaia immunologiia. 2004;6(1-1):67-74. (In Russ.)]
  34. Pawlica-Gosiewska D, Solnica B, Gawlik K, et al. The use of selected neutrophil protein plasma concentrations in the diagnosis of Crohn’s disease and ulcerative colitis – a preliminary report. Postepy Hig Med Dosw (Online). 2017;71(1):0-0.
  35. Fillebeen C, Ruchoux M-M, Mitchell V, et al. Lactoferrin is synthesized by activated microglia in the human substantia nigra and its synthesis by the human microglial CHME cell line is upregulated by tumor necrosis factor α or 1-methyl-4-phenylpyridinium treatment. Brain Res Mol Brain Res. 2001;96(1-2):103-113.
  36. Valenti P, Antonini G. Lactoferrin: an important host defence against microbial and viral attack. Cell Mol Life Sci. 2005;62(22):2576-2587.
  37. Puddu P, Valenti P, Gessani S. Immunomodulatory effects of lactoferrin on antigen presenting cells. Biochimie. 2009;91(1):11-18.
  38. Puddu P, Latorre D, Carollo M, et al. Bovine lactoferrin counteracts Toll-like receptor mediated activation signals in antigen presenting cells. PLoS One. 2011;6(7):e22504.
  39. Saito H, Miyakawa H, Tamura Y, et al. Potent Bactericidal Activity of Bovine Lactoferrin Hydrolysate Produced by Heat Treatment at Acidic pH. J Dairy Sci. 1991;74(11):3724-3730.
  40. Yamauchi K, Tomita M, Giehl TJ, Ellison RT, 3rd. Antibacterial activity of lactoferrin and a pepsin-derived lactoferrin peptide fragment. Infect Immun. 1993;61(2):719-728.
  41. Di Biase AM, Tinari A, Pietrantoni A, et al. Effect of bovine lactoferricin on enteropathogenic Yersinia adhesion and invasion in HEp-2 cells. J Med Microbiol. 2004;53(Pt 5):407-412.
  42. Tomita M, Takase M, Wakabayashi H, Bellamy W. Antimicrobial peptides of lactoferrin. Adv Exp Med Biol. 1994;357:209-218.
  43. Hwang PM, Zhou N, Shan X, et al. Three-dimensional solution structure of lactoferricin B, an antimicrobial peptide derived from bovine lactoferrin. Biochemistry. 1998;37(12):4288-4298.
  44. Hunter HN, Demcoe AR, Jenssen H, et al. Human lactoferricin is partially folded in aqueous solution and is better stabilized in a membrane mimetic solvent. Antimicrob Agents Chemother. 2005;49(8):3387-3395.
  45. Kuwata H, Yip TT, Tomita M, et al. Direct evidence of the generation in human stomach of an antimicrobial peptide domain (lactoferricin) from ingested lactoferrin. Biochim Biophys Acta. 1998;1429(1):129-141.
  46. Kuwata H, Yamauchi K, Teraguchi S, et al. Functional fragments of ingested lactoferrin are resistant to proteolytic degradation in the gastrointestinal tract of adult rats. J Nutr. 2001;131(8):2121-2127.
  47. Andres MT, Fierro JF. Antimicrobial mechanism of action of transferrins: selective inhibition of H+-ATPase. Antimicrob Agents Chemother. 2010;54(10):4335-4342.
  48. Sessa R, Di Pietro M, Filardo S, et al. Effect of bovine lactoferrin on Chlamydia trachomatis infection and inflammation. Biochem Cell Biol. 2017;95(1):34-40.
  49. Lu L, Hangoc G, Oliff A, et al. Protective influence of lactoferrin on mice infected with the polycythemia-inducing strain of Friend virus complex. Cancer Res. 1987;47(15):4184-4188.
  50. Broxmeyer HE, Williams DE, Hangoc G, et al. The opposing actions in vivo on murine myelopoiesis of purified preparations of lactoferrin and the colony stimulating factors. Blood Cells. 1987;13(1-2):31-48.
  51. Bezault J, Bhimani R, Wiprovnick J, Furmanski P. Human lactoferrin inhibits growth of solid tumors and development of experimental metastases in mice. Cancer Res. 1994;54(9):2310-2312.
  52. Hayes TG, Falchook GF, Varadhachary GR, et al. Phase I trial of oral talactoferrin alfa in refractory solid tumors. Invest New Drugs. 2006;24(3):233-240.
  53. Sakai T, Banno Y, Kato Y, et al. Pepsin-Digested Bovine Lactoferrin Induces Apoptotic Cell Death With JNK/SAPK Activation in Oral Cancer Cells. J Pharmacol Sci. 2005;98(1):41-48.
  54. Tsuda H, Sekine K, Fujita K-i, Iigo M. Cancer prevention by bovine lactoferrin and underlying mechanisms: a review of experimental and clinical studies. Biochem Cell Biol. 2002;80(1):131-136.
  55. Gahr M, Speer CP, Damerau B, Sawatzki G. Influence of Lactoferrin on the Function of Human Polymorphonuclear Leukocytes and Monocytes. J Leukoc Biol. 1991;49(5):427-433.
  56. Wang W-P, Iigo M, Sato J, et al. Activation of Intestinal Mucosal Immunity in Tumor-bearing Mice by Lactoferrin. Jpn J Cancer Res. 2000;91(10):1022-1027.
  57. Artym J, Zimecki M, Kruzel ML. Effect of lactoferrin on the methotrexate-induced suppression of the cellular and humoral immune response in mice. Anticancer Res. 2004;24(6):3831-3836.
  58. Britigan BE, Serody JS, Cohen MS. The Role of Lactoferrin as an Anti-Inflammatory Molecule. Lactoferrin. 1994;357:143-156.
  59. Appelmelk BJ, An YQ, Geerts M, et al. Lactoferrin is a lipid A-binding protein. Infect Immun. 1994;62(6):2628-2632.
  60. Elass-Rochard E, Legrand D, Salmon V, et al. Lactoferrin inhibits the endotoxin interaction with CD14 by competition with the lipopolysaccharide-binding protein. Infect Immun. 1998;66(2):486-491.
  61. Baveye S, Elass E, Fernig DG, et al. Human Lactoferrin Interacts with Soluble CD14 and Inhibits Expression of Endothelial Adhesion Molecules, E-Selectin and ICAM-1, Induced by the CD14-Lipopolysaccharide Complex. Infect Immun. 2000;68(12):6519-6525.
  62. Zagulski T, Lipinski P, Zagulska A, et al. Lactoferrin can protect mice against a lethal dose of Escherichia coli in experimental infection in vivo. Br J Exp Pathol. 1989;70(6):697-704.
  63. Machnicki M, Zimecki M, Zagulski T. Lactoferrin regulates the release of tumour necrosis factor alpha and interleukin 6 in vivo. Int J Exp Pathol. 1993;74(5):433-439.
  64. Bennett RM, Kokocinski T. Lactoferrin Turnover in Man. Clin Sci (Lond). 1979;57(5):453-460.
  65. Retegui LA, Moguilevsky N, Castracane CF, et al. Uptake of lactoferrin by the liver. I. Role of the reticuloendothelial system as indicated by blockade experiments. Lab Invest. 1984;50(3):323-328.
  66. Curran CS, Demick KP, Mansfield JM. Lactoferrin activates macrophages via TLR4-dependent and -independent signaling pathways. Cell Immunol. 2006;242(1):23-30.
  67. Håversen L, Ohlsson BG, Hahn-Zoric M, et al. Lactoferrin down-regulates the LPS-induced cytokine production in monocytic cells via NF-κB. Cell Immunol. 2002;220(2):83-95.
  68. Yoshimaki T, Sato S, Tsunori K, et al. Bone regeneration with systemic administration of lactoferrin in non-critical-sized rat calvarial bone defects. J Oral Sci. 2013;55(4):343-348.
  69. Kimber I, Cumberbatch M, Dearman RJ, et al. Lactoferrin and regulation of cutaneous immunity and inflammation. In: Lactoferrin: Structure, Functions and Aplications. Elsevier Science B.V.; 2000. P. 87-93.
  70. Kimber I, Cumberbatch M, Dearman RJ, et al. Lactoferrin: influences on Langerhans cells, epidermal cytokines, and cutaneous inflammation. Biochemistry and Cell Biology. 2002;80(1):103-107.
  71. Duthille I, Masson M, Spik G, Mazurier J. Lactoferrin stimulates the mitogen-activated protein kinase in the human lymphoblastic T Jurkat cell line. Adv Exp Med Biol. 1998;443:257-260.
  72. Mikkelsen TL, Bakman S, Sorensen ES, et al. Sialic acid-containing milk proteins show differential immunomodulatory activities independent of sialic acid. J Agric Food Chem. 2005;53(20):7673-7680.
  73. Brock J. Lactoferrin: a multifunctional immunoregulatory protein? Immunol Today. 1995;16(9):417-419.
  74. Zimecki M, Mazurier J, Spik G, Kapp JA. Human lactoferrin induces phenotypic and functional changes in murine splenic B cells. Immunology. 1995;86(1):122-127.
  75. Zimecki M, Mazurier J, Spik G, Kapp JA. Lactoferrin inhibits proliferative response and cytokine production of TH1 but not TH2 cell lines. Arch Immunol Ther Exp (Warsz). 1996;44(1):51-56.
  76. Guillen C, McInnes IB, Vaughan DM, et al. Enhanced Th1 Response to Staphylococcus aureus Infection in Human Lactoferrin-Transgenic Mice. J Immunol. 2002;168(8):3950-3957.
  77. Hwang SA, Kruzel ML, Actor JK. Lactoferrin augments BCG vaccine efficacy to generate T helper response and subsequent protection against challenge with virulent Mycobacterium tuberculosis. Int Immunopharmacol. 2005;5(3):591-599.
  78. Zakharova ET, Kostevich VA, Sokolov AV, Vasilyev VB. Human apo-lactoferrin as a physiological mimetic of hypoxia stabilizes hypoxia-inducible factor-1 alpha. Biometals. 2012;25(6):1247-1259.
  79. Zakharova ET, Sokolov AV, Pavlichenko NN, et al. Erythropoietin and Nrf2: key factors in the neuroprotection provided by apo-lactoferrin. Biometals. 2018;31(3):425-443.
  80. He J, Furmanski P. Sequence specificity and transcriptional activation in the binding of lactoferrin to DNA. Nature. 1995;373(6516):721-724.
  81. Garre C, Bianchi-Scarra G, Sirito M, et al. Lactoferrin binding sites and nuclear localization in K562(S) cells. J Cell Physiol. 1992;153(3):477-482.
  82. Son KN, Park J, Chung CK, et al. Human lactoferrin activates transcription of IL-1beta gene in mammalian cells. Biochem Biophys Res Commun. 2002;290(1):236-241.
  83. Mariller C, Hardiville S, Hoedt E, et al. Delta-lactoferrin, an intracellular lactoferrin isoform that acts as a transcription factor. Biochem Cell Biol. 2012;90(3):307-319.
  84. Suzuki YA, Lopez V, Lonnerdal B. Mammalian lactoferrin receptors: structure and function. Cell Mol Life Sci. 2005;62(22):2560-2575.
  85. Legrand D, Vigie K, Said EA, et al. Surface nucleolin participates in both the binding and endocytosis of lactoferrin in target cells. Eur J Biochem. 2004;271(2):303-317.
  86. Meilinger M, Haumer M, Szakmary KA, et al. Removal of lactoferrin from plasma is mediated by binding to low density lipoprotein receptor-related protein/α 2-macroglobulin receptor and transport to endosomes. FEBS Lett. 1995;360(1):70-74.
  87. Legrand D, Mazurier J. A critical review of the roles of host lactoferrin in immunity. Biometals. 2010;23(3):365-376.
  88. Ken A, Keiichi H, Takafumi S, et al. TLR4-dependent regulation of intestinal immune responses by lactoferrin. (Conference proceedigs) XI International Conference on Lactoferrin Structure, Function & Applications; 2013 oct 6-10; Rome. Rome.
  89. Legrand D. Lactoferrin, a key molecule in immune and inflammatory processes. Biochem Cell Biol. 2012;90(3):252-268.
  90. Zimecki M, Artym J, Kocieba M. Endogenous steroids are responsible for lactoferrin-induced myelopoiesis in mice. Pharmacol Rep. 2009;61(4):705-710.
  91. Rousseau E, Michel PP, Hirsch EC. The iron-binding protein lactoferrin protects vulnerable dopamine neurons from degeneration by preserving mitochondrial calcium homeostasis. Mol Pharmacol. 2013;84(6):888-898.
  92. Zimecki M, Artym J, Chodaczek G, et al. Effects of lactoferrin on the immune response modified by the immobilization stress. Pharmacol Rep. 2005;57(6):811-817.
  93. Kamemori N, Takeuchi T, Hayashida K, Harada E. Suppressive effects of milk-derived lactoferrin on psychological stress in adult rats. Brain Res. 2004;1029(1):34-40.
  94. Shumake J, Barrett DW, Lane MA, Wittke AJ. Behavioral effects of bovine lactoferrin administration during postnatal development of rats. Biometals. 2014;27(5):1039-1055.
  95. McManus B, Korpela R, O’Connor P, et al. Compared to casein, bovine lactoferrin reduces plasma leptin and corticosterone and affects hypothalamic gene expression without altering weight gain or fat mass in high fat diet fed C57/BL6J mice. Nutr Metab (Lond). 2015;12:53.
  96. Алешина Г.М., Янкелевич И.А., Кокряков В.Н. Лактоферрин человека модулирует экспрессию гена рецептора TLR4 в селезенке крысы в условиях экспериментального стресса // Российский иммунологический журнал. – 2016. – Т. 10. – № 2. – С. 60–62. [Aleshina GM, Yankelevich IA, Kokryakov VN. Laktoferrin cheloveka moduliruet ekspressiyu gena retseptora TLR4 v selezenke krysy v usloviyakh eksperimental’nogo stressa. Ross Immunol Zhurnal. 2016;10(2):60-62. (In Russ.)]
  97. Алешина Г.М., Янкелевич И.А., Захарова Е.Т., и др. Стресс-протективное действие лактоферрина человека // Российский физиологический журнал им. И.М. Сеченова. – 2016. – Т. 102. – № 7. – С. 846–851. [Aleshina GM, Yankelevich IA, Zakharova ET, et al. Stress-protective effect of human lactoferrin. Ross Fiziol Zh Im I M Sechenova. 2016;102(7):846-851. (In Russ.)]
  98. Maekawa Y, Sugiyama A, Takeuchi T. Lactoferrin ameliorates corticosterone-related acute stress and hyperglycemia in rats. J Vet Med Sci. 2017;79(2):412-417.

Supplementary files

Supplementary Files Action
1. Fig. 1. Ribbon diagram of human lactoferrin. The N-lobe is on the left, with its bound Fe3+ and CO32– ions (shown as spherical atoms, indicated by arrows) in the cleft between the two domains, N1 and N2. Similarly, for the C-lobe (right) the C1 and C2 domains with the Fe3+ and CO32– ions in between. The two lobes are joined by a three-turn helix [19] View (110KB) Indexing metadata


Abstract - 47

PDF (Russian) - 0




  • There are currently no refbacks.

Copyright (c) 2019 Aleshina G.M.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.