, Volume 17, Issue 3, pp 203–208 | Cite as

Lactoferrin: Role in iron homeostasis and host defense against microbial infection

  • Pauline P. Ward
  • Oria M. ConneelyEmail author


The transferrin family of non-heme iron binding glycoproteins are believed to play a central role in iron metabolism and have been implicated in iron transport, cellular iron delivery and control of the level of free iron in external secretions. Lactoferrin (LF) is a member of this family that is widely localized in external fluids including milk and mucosal secretions, in addition to being a prominent component of the secondary granules of neutrophils. Although structurally related to transferrin, LF appears to have a broader functional role mediated by both iron dependent and iron independent mechanisms. In this review, we will focus on our current understanding on the role of LF in regulating iron homeostasis and its role in host protection against microbial infection at the mucosal surface. In addition, recent insights obtained from analyzing the phenotypic consequences of LF ablation in lactoferrin knockout mice (LFKO), which challenge the long held dogma that LF is required for intestinal iron absorption in the neonate, are summarized.

antimicrobial activity host defense iron lactoferrin 


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  1. Ahmad KA, Ahmann JR, Migas MC et al. 2002 Decreased liver hepcidin expression in the hfe knockout mouse. Blood Cells Mol Dis 29, 361-366.PubMedGoogle Scholar
  2. Aisen P, Listowsky I. 1980 Iron transport and storage proteins. Annu Rev Biochem 49, 357-393.PubMedGoogle Scholar
  3. Ajello M, Greco R, Giansanti F et al. 2002 Anti-invasive activity of bovine lactoferrin towards group A streptococci. Biochem Cell Biol 80, 119-124.PubMedGoogle Scholar
  4. Anderson BF, Baker HM, Dodson EJ et al. 1987 Structure of human lactoferrin at 3.2-A resolution. Proc Natl Acad Sci USA 84, 1769-1773.PubMedGoogle Scholar
  5. Anderson BF, Baker HM, Norris GE, Rice DW, Baker EN. 1989 Structure of human lactoferrin: crystallographic structure analysis and refinement at 2.8 A resolution. J Mol Biol 209, 711-734.PubMedGoogle Scholar
  6. Andrews NC. 2000 Iron homeostasis: insights from genetics and animal models. Nat Rev Genet 1, 208-217.PubMedGoogle Scholar
  7. Baker HM, Anderson BF, Baker EN. 2003 Dealing with iron: common structural principles in proteins that transport iron and heme. Proc Natl Acad Sci USA 100, 3579-3583.PubMedGoogle Scholar
  8. Baveye S, Elass E, Mazurier J, Spik G, Legrand D. 1999 Lactoferrin: a multifunctional glycoprotein involved in the modulation of the inflammatory process. Clin Chem Lab Med 37, 281-286.PubMedGoogle Scholar
  9. Bellamy W, Takase M, Yamauchi K et al. 1992 Identification of the bactericidal domain of lactoferrin. Biochim Biophys Acta 1121, 130-136.PubMedGoogle Scholar
  10. Bernstein SE. 1987 Hereditary hypotransferrinemia with hemosiderosis, a murine disorder resembling human atransferrinemia. J Lab Clin Med 110, 690-705.PubMedGoogle Scholar
  11. Brock JH. 1980 Lactoferrin in human milk: its role in iron absorption and protection against enteric infection in the newborn infant. Arch Dis Child 55, 417-421.PubMedGoogle Scholar
  12. Brock JH. 2002 The physiology of lactoferrin. Biochem Cell Biol 80, 1-6.Google Scholar
  13. Crosa JH. 1989 Genetics and molecular biology of siderophoremediated iron transport in bacteria. Microbiol Rev 53, 517-530.PubMedGoogle Scholar
  14. Davidsson L, Kastenmayer P, Yuen M, Lonnerdal B, Hurrell RF. 1994 Influence of lactoferrin on iron absorption from human milk in infants. Pediatr Res 35, 117-124.PubMedGoogle Scholar
  15. Ellison RT 3rd, Giehl TJ. 1991 Killing of gram-negative bacteria by lactoferrin and lysozyme. J Clin Invest 88, 1080-1091.PubMedGoogle Scholar
  16. Fleming MD, Romano MA, Su MA et al. 1998 Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci USA 95, 1148-1153.PubMedGoogle Scholar
  17. Fleming MD, Trenor CC, 3rd, Su MA et al. 1997 Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet 16, 383-386.PubMedGoogle Scholar
  18. Fleming RE, Sly WS. 2001 Hepcidin: a putative iron-regulatory hormone relevant to hereditary hemochromatosis and the anemia of chronic disease. Proc Natl Acad Sci USA 98, 8160-8162.PubMedGoogle Scholar
  19. Fleming RE, Sly WS. 2002 Mechanisms of iron accumulation in hereditary hemochromatosis. Annu Rev Physiol 64, 663-680.PubMedGoogle Scholar
  20. Frazer DM, Anderson GJ. 2003 The orchestration of body iron intake: how and where do enterocytes receive their cues? Blood Cells Mol Dis 30, 288-297.PubMedGoogle Scholar
  21. Ganz T. 2003 Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood.Google Scholar
  22. Gomez HF, Ochoa TJ, Carlin LG, Cleary TG. 2003 Human lactoferrin impairs virulence of Shigella flexneri. J Infect Dis 187, 87-95.PubMedGoogle Scholar
  23. Goya N, Miyazaki S, Kodate S, Ushio B. 1972 A family of congenital atransferrinemia. Blood 40, 239-245.PubMedGoogle Scholar
  24. Gunshin H, Mackenzie B, Berger UV et al. 1997 Cloning and characterization of amammalian proton-coupled metal-ion transporter. Nature 388, 482-488.PubMedGoogle Scholar
  25. Hennart PF, Brasseur DJ, Delogne-Desnoeck JB, Dramaix MM, Robyn CE. 1991 Lysozyme, lactoferrin, and secretory immunoglobulin A content in breast milk: influence of duration of lactation, nutrition status, prolactin status, and parity of mother. Am J Clin Nutr 53, 32-39.PubMedGoogle Scholar
  26. Iyer S, Lonnerdal B. 1993 Lactoferrin, lactoferrin receptors and iron metabolism. Eur J Clin Nutr 47, 232-241.PubMedGoogle Scholar
  27. Kawakami H, Lonnerdal B. 1991 Isolation and function of a receptor for human lactoferrin in human fetal intestinal brushborder membranes. Am J Physiol 261, G841-846.PubMedGoogle Scholar
  28. Lee JK, Schnee J, Pang M et al. 2001 Human homologs of the Xenopus oocyte cortical granule lectin XL35. Glycobiology 11, 65-73.PubMedGoogle Scholar
  29. Leitch EC, Willcox MD. 1998 Synergic antistaphylococcal properties of lactoferrin and lysozyme. J Med Microbiol 47, 837-842.PubMedGoogle Scholar
  30. Levay PF, Viljoen M. 1995 Lactoferrin: a general review. Haematologica 80, 252-267.PubMedGoogle Scholar
  31. Levy JE, Jin O, Fujiwara Y, Kuo F, Andrews NC. 1999 Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat Genet 21, 396-399.PubMedGoogle Scholar
  32. Longhi C, Conte MP, Seganti L et al. 1993 Influence of lactoferrin on the entry process of Escherichia coli HB101 (pRI203) in HeLa cells. Med Microbiol Immunol (Berl) 182, 25-35.Google Scholar
  33. Masson PL, Heremans JF. 1971 Lactoferrin in milk from different species. Comp Biochem Physiol B 39, 119-129.PubMedGoogle Scholar
  34. Masson PL, Heremans JF, Schonne E. 1969 Lactoferrin, an ironbinding protein in neutrophilic leukocytes. J ExpMed 130, 643-658.Google Scholar
  35. Masson PL, Heremans, JF, Dive C. 1966 An iron-binding protein common to many external secretions. Clinica Chimica Acta 14, 735-739.Google Scholar
  36. Metz-Boutigue MH, Jolles J, Mazurier J et al. 1984 Human lactotransferrin: amino acid sequence and structural comparisons with other transferrins. Eur J Biochem 145, 659-676.PubMedGoogle Scholar
  37. Morgan EH, Oates PS. 2002 Mechanisms and regulation of intestinal iron absorption. Blood Cells Mol Dis 29, 384-399.PubMedGoogle Scholar
  38. Muckenthaler M, Roy CN, Custodio AO et al. 2003 Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Nat Genet 34, 102-107.PubMedGoogle Scholar
  39. Nicolas G, Bennoun M, Devaux I et al. 2001 Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci USA 98, 8780-8785.PubMedGoogle Scholar
  40. Nicolas G, Bennoun M, Porteu A et al. 2002 Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci USA 99, 4596-4601.PubMedGoogle Scholar
  41. Nicolas G, Viatte L, Lou DQ et al. 2003 Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat Genet 34, 97-101.PubMedGoogle Scholar
  42. Petschow BW, Talbott RD and Batema RP. 1999 Ability of lactoferrin to promote the growth of Bifidobacterium spp. in vitro is independent of receptor binding capacity and iron saturation level. J Med Microbiol 48, 541-549.PubMedGoogle Scholar
  43. Pigeon C, Ilyin G, Courselaud B et al. 2001 A new mouse liverspecific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 276, 7811-7819.PubMedGoogle Scholar
  44. Qiu J, Hendrixson DR, Baker EN et al. 1998 Humanmilk lactoferrin inactivates two putative colonization factors expressed by Haemophilus influenzae. Proc Natl Acad Sci USA 95, 12641-12646.PubMedGoogle Scholar
  45. Roetto A, Papanikolaou G, Politou M et al. 2003 Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet 33, 21-22.PubMedGoogle Scholar
  46. Sanchez L, Calvo M, Brock JH. 1992 Biological role of lactoferrin. Arch Dis Child 67, 657-661.PubMedGoogle Scholar
  47. Schaible UE, Collins HL, Priem F, Kaufmann SH. 2002 Correction of the iron overload defect in beta-2-microglobulin knockout mice by lactoferrin abolishes their increased susceptibility to tuberculosis. J ExpMed 196, 1507-1513.Google Scholar
  48. Schryvers AB, Bonnah R, Yu RH, Wong H, Retzer M. 1998 Bacterial lactoferrin receptors. Adv Exp Med Biol 443, 123-133.PubMedGoogle Scholar
  49. Singh PK, Parsek MR, Greenberg EP, Welsh MJ. 2002 A component of innate immunity prevents bacterial biofilm development. Nature 417, 552-555.PubMedGoogle Scholar
  50. Singh PK, Tack BF, McCray PB Jr., Welsh MJ. 2000 Synergistic and additive killing by antimicrobial factors found in human airway surface liquid. Am J Physiol Lung Cell Mol Physiol 279, L799-805.PubMedGoogle Scholar
  51. Suzuki YA, Shin K, Lonnerdal B. 2001 Molecular cloning and functional expression of a human intestinal lactoferrin receptor. Biochemistry 40, 15771-15779.PubMedGoogle Scholar
  52. Tsuji S, Uehori J, Matsumoto M et al. 2001 Human intelectin is a novel soluble lectin that recognizes galactofuranose in carbohydrate chains of bacterial cell wall. J Biol Chem 276, 23456-23463.PubMedGoogle Scholar
  53. Valenti P, Marchetti M, Superti F et al. 1998 Antiviral activity of lactoferrin. Adv Exp Med Biol 443, 199-203.PubMedGoogle Scholar
  54. van der Strate BW, Beljaars L, Molema G, Harmsen MC, Meijer DK. 2001 Antiviral activities of lactoferrin. Antiviral Res 52, 225-239.PubMedGoogle Scholar
  55. van Renswoude J, Bridges KR, Harford JB, Klausner RD. 1982 Receptor-mediated endocytosis of transferrin and the uptake of fe in K562 cells: identification of a nonlysosomal acidic compartment. Proc Natl Acad Sci USA 79, 6186-6190.PubMedGoogle Scholar
  56. Wakabayashi H, Takase M, Tomita M. 2003 Lactoferricin derived from milk protein lactoferrin. Curr Pharm Des 9, 1277-1287.PubMedGoogle Scholar
  57. Ward PP, Mendoza-Meneses M, Cunningham GA, Conneely OM. 2003 Iron status in mice carrying a targeted disruption of lactoferrin. Mol Cell Biol 23, 178-185.PubMedGoogle Scholar
  58. Ward PP, Uribe-Luna S, Conneely OM. 2002 Lactoferrin and host defense. Biochem Cell Biol 80, 95-102.PubMedGoogle Scholar
  59. Weinstein DA, Roy CN, Fleming MD et al. 2002 Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood 100, 3776-3781.PubMedGoogle Scholar
  60. Wessling-Resnick M. 2000 Iron transport. Annu Rev Nutr 20, 129-151.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  1. 1.Department of Molecular and Cellular BiologyBaylor College of MedicineHoustonUSA

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