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Structure and biological actions of lactoferrin

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Abstract

Lactoferrin is an iron-binding glycoprotein of the transferrin family, first isolated from milk but also found in most exocrine secretions as well as in the secondary granules of neutrophils. The many reports on its antimicrobial and antiinflammatory activityin vitro identify lactoferrin as important in host defense against infection and excessive inflammation. Most if not all lactoferrin actions are mediated through iron sequestration and/or interaction with a large variety of ligands including microbial cell wall components and cellular receptors, through its highly positively charged N-terminus. Lactoferrin exerts its effects on glandular epithelia, secretions, mucosal surfaces as well as in the interstitium and vascular compartments where it has been postulated to participate in iron metabolism, disease defense, and modulation of inflammatory and immune responses. A need to understand the diverse biological actions of lactoferrin and the prospect of a wide variety of potential applications in human health care have stimulated studies of the relation between lactoferrin structure and function, the regulation of lactoferrin secretion and development of large scale production of recombinant human lactoferrin (hLf). This review provides a synthesis of our current understanding of lactoferrin. Space limitations have led us to refer to review articles whenever possible; the reader is advised to use these articles for access to the primary experimental literature.

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Abbreviations

hLf:

human lactoferrin

bLf:

bovine lactoferrin

mLf:

murine lactoferrin

rhLf:

recombinant hLf

LPS:

lipopolysaccharide

NK:

natural killer

References

  1. B. Lönnerdal and S. Iyer (1995). Lactoferrin molecular structure and biological function.Ann. Rev. Nutr. 15:93–110.

    Google Scholar 

  2. F. L. Schanbacher, R. E. Goodman, and R. S. Talhouk (1993). Bovine mammary lactoferrin: implications from messenger ribonucleic acid (mRNA) sequence and regulation contrary to other milk proteins.J. Dairy Sci. 76:3812–3831.

    PubMed  Google Scholar 

  3. E. N. Baker, B. F. Anderson, H. M. Baker, C. L. Day, M. Haridas, G. E. Norris, S. V. Rumball, C. A. Smith, and D. H. Thomas (1994). Three-dimensional structure of lactoferrin in various functional states.Adv. Exp. Med. Biol. 357:1–12.

    PubMed  Google Scholar 

  4. R. R. Crichton (1990). Proteins of iron storage and transport.Adv. Prot. Chem. 40:281–363.

    Google Scholar 

  5. T. T. Yip and T. W. Hutchens (1994). Interaction of lactoferrin with sequestered transition metal ions.Adv. Exp. Med. Biol. 357:53–60.

    PubMed  Google Scholar 

  6. C. Mantel, K. Miyazawa, and H. E. Broxmeyer (1994). Physical characteristics and polymerization during iron saturation of lactoferrin, a myelopoietic regulatory molecule with suppressor activity.Adv. Exp. Med. Biol. 357:121–132.

    PubMed  Google Scholar 

  7. X. Y. Zhao and T. W. Hutchens (1994). Proposed mechanisms for the involvement of lactoferrin in the hydrolysis of nucleic acids.Adv. Exp. Med. Biol. 357:271–278.

    PubMed  Google Scholar 

  8. P. H. C. Van Berkel, M. E. J. Geerts, H. A. van Veen, P. M. Kooiman, F. Pieper, H. A. de Boer, and J. H. Nuijens (1995). Glycosylated and unglycosylated human lactoferrins can both bind iron and have identical affinities towards human lysozyme and bacterial lipopolysaccharide, but differ in their susceptibility towards tryptic proteolysis.Biochem. J. 312:107–114.

    PubMed  Google Scholar 

  9. L. Sanchez, M. Calvo, and J. H. Brock (1992). Biological role of lactoferrin.Arch. Dis. Child. 67:657–661.

    PubMed  Google Scholar 

  10. E. Elass-Rochard, A. Roseanu, D. Legrand, M. Trif, V. Salmon, C. Motas, J. Montreuil, and G. Spik (1995). Lactoferrin-lipopolysaccharide interactions: involvement of the 28–34 loop region of human lactoferrin in the high-affinity binding ofEschericia coli 055B5 lipopolysaccharide.Biochem. J. 312:839–846.

    PubMed  Google Scholar 

  11. K. Miyazawa, C. Mantel, L. Lu, D. C. Morrison, and H. E. Broxmeyer (1991). Lactoferrin-lipopolysaccharide interactions. Effect on lactoferrin binding to monocyte/macrophage-differentiated HL-60 cells.J. Immunol. 146:723–729.

    PubMed  Google Scholar 

  12. J. He and P. Furmanski (1995). Sequence specificity and transcriptional activation in the binding of lactoferrin to DNA.Nature 373:721–724.

    PubMed  Google Scholar 

  13. D. M. Mann, E. Romm, and M. Migliorini (1994). Delineation of the glycosaminoglycan-binding site in the human inflammatory response protein lactoferrin.J. Biol. Chem. 269:23661–23667.

    PubMed  Google Scholar 

  14. J. Mazurier, D. Legrand, B. Leveugle, E. Rochard, J. Montreuil, and G. Spik (1994). Study on the binding of lactotransferrin (lactoferrin) to human PHA-activated lymphocytes and non-activated platelets. Localisation and description of the receptor-binding site.Adv. Exp. Med. Biol. 357:111–119.

    PubMed  Google Scholar 

  15. G. Spik, B. Coddeville, J. Mazurier, Y. Bourne, C. Cambillaut, and J. Montreuil (1994). Primary and three-dimensional structure of lactotransferrin (lactoferrin) glycans.Adv. Exp. Med. Biol. 357:21–32.

    PubMed  Google Scholar 

  16. R. Chierici and V. Vigi (1994). Lactoferrin in infant formulae.Acta Pediatr. Suppl. 402:83–88.

    Google Scholar 

  17. R. T. Ellison, III (1994). The effects of lactoferrin on Gramnegative bacteria.Adv. Exp. Med. Biol. 357:71–90.

    PubMed  Google Scholar 

  18. M. O. Husson, D. Legrand, G. Spik, and H. Leclerc (1993). Iron acquisition by Helicobacter pylori: importance of human lactoferrin.Infect. Immun. 61:2694–2697.

    PubMed  Google Scholar 

  19. M. C. Harmsen, P. J. Swart, M. P. de Béthune, R. Pauwels, E. De Clercq, T. Hauw The, and D. F. K. Meijer (1995). Antiviral effects of plasma and milk proteins: lactoferrin shows potent activity against both human immunodeficiency virus and human cytomegalovirus replicationin vitro.J. Infect. Dis. 172:380–388.

    PubMed  Google Scholar 

  20. M. Tomita, M. Takase, H. Wakabayashi, and W. Bellamy (1994). Antimicrobial peptides of lactoferrin.Adv. Exp. Med. Biol. 357:209–218.

    PubMed  Google Scholar 

  21. H. F. Wu, R. L. Lundblad, and F. C. Church (1995). Neutralization of heparin activity by neutrophil lactoferrin.Blood 85:421–428.

    PubMed  Google Scholar 

  22. A. Kijlstra (1990). The role of lactoferrin in the nonspecific immune response on the ocular surface.Reg. Immunol. 3:193–197.

    PubMed  Google Scholar 

  23. P. Ferenc Levay and M. Viljoen (1995). Lactoferrin: a general review.Hematologica 80:252–267.

    Google Scholar 

  24. J. Levin, S. J. H. van Deventer, T. van der Poll, and A. Sturk (1994).Bacterial Endotoxins. Basic Science to Anti-sepsis Strategies. Progress in Clinical and Biological Research (Vol. 388), John Wiley and Sons.

  25. D. Wang, K. M. Pabst, Y. Aida, and M. J. Pabst (1995). Lipopolysaccharide-inactivating activity of neutrophils is due to lactoferrin.J. Leuk. Biol. 57:865–874.

    Google Scholar 

  26. I. Kurose, T. Yamada, R. Wolf, and D. N. Granger (1994). P-selectin-dependent leukocyte recruitment and intestinal mucosal injury induced by lactoferrin.J. Leuk. Biol. 55:771–777.

    Google Scholar 

  27. U. K. Misra, C. T. Chu, G. Gawdi, and S. V. Pizzo (1994). The relationship between low density lipoprotein-related protein/alpha 2-macroglobulin (alpha 2M) receptors and the newly described alpha 2M signaling receptor.J. Biol. Chem. 269:18303–18306.

    PubMed  Google Scholar 

  28. H. Shau, A. Kim, and S. H. Golub (1992). Modulation of natural killer and lymphokine-activated killer cell cytotoxicity by lactoferrin.J. Leuk. Biol. 51:343–349.

    Google Scholar 

  29. J. Bezault, R. Bhimani, J. Wiprovnick, and P. Furmanski (1994). Human lactoferrin inhibits growth of solid tumors and development of experimental metastases in mice.Cancer Res. 54:2310–2312.

    PubMed  Google Scholar 

  30. S. Penco, S. Pastorino, S. G. Bianchi, and C. Garre (1995). Lactoferrin down-modulates the activity of the granulocyte macrophage colony-stimulating factor promoter in interleukin-1 beta-stimulated cells.J. Biol. Chem. 270:12263–12268.

    PubMed  Google Scholar 

  31. S. Oguchi, W. A. Walker, and I. R. Sanderson (1995). Iron saturation alters the effect of lactoferrin on the proliferation and differentiation of human enterocytes (Caco-2 cells).Biol. Neonate 67:330–339.

    PubMed  Google Scholar 

  32. P. P. Ward, C. S. Piddington, G. A. Cunningham, X. Zhou, R. D. Wyatt, and O. M. Conneely (1995). A system for the production of commercial quantities of human lactoferrin: a broad spectrum natural antibiotic.Bio/Technology 13:498–503.

    PubMed  Google Scholar 

  33. T. Mikogami, T. Marianne, and G. Spik (1995). Effect of intracellular iron depletion by picolinic acid on expression of the lactoferrin receptor in the human colon carcinoma cell subclone HT29-18-Cl.Biochem. J. 308:391–397.

    PubMed  Google Scholar 

  34. G. J. Ziere, M. K. Bijsterbosch, and T. J. van Berkel (1993). Removal of 14 N-terminal amino acids of lactoferrin enhances its affinity for parenchymal liver cells and potentiates the inhibition of beta- very low density lipoprotein binding.J. Biol. Chem. 268:27069–27075.

    PubMed  Google Scholar 

  35. D. D. McAbee (1995). Isolated rat hepatocytes acquire iron from lactoferrin by endocytosis.Biochem. J. 311:603–609.

    PubMed  Google Scholar 

  36. C. T. Teng (1994). Lactoferrin gene promoter in human and mouse. Analogous and dissimilar characteristics.Adv. Exp. Med. Biol. 357:183–196.

    PubMed  Google Scholar 

  37. A. J. Molenaar, S. R. Davis, and R. J. Wilkins (1992). Expression of alpha-lactalbumin, alpha-S1-casein, and lactoferrin genes is heterogeneous in sheep and cattle mammary tissue.J. Histochem. Cytochem. 40:611–618.

    PubMed  Google Scholar 

  38. W. L. Hurley and J. J. Rejman (1993). Bovine lactoferrin in involuting mammary tissue.Cell. Biol. Int. 17:283–289.

    PubMed  Google Scholar 

  39. H. M. Seyfert, A. Tuckoricz, H. Interthal, D. Koczan, and G. Hobom (1994). Structure of the bovine lactoferrin-encoding gene and its promoter.Gene 143:265–269.

    PubMed  Google Scholar 

  40. H. Shi and C. T. Teng (1994). Characterization of a mitogen-response unit in the mouse lactoferrin gene promoter.J. Biol. Chem. 269:12973–12980.

    PubMed  Google Scholar 

  41. F. L. Schanbacher, S. Pattanajitvilai, and M. C. Neville (1995). Posttranslational regulation of bovine and human lactoferrin: species differences and influence of mRNA regions.Proc. 2nd Int'l. Conf. on Structure and Function of LF (submitted).

  42. G. J. Platenburg, E. P. Kootwijk, P. M. Kooiman, S. L. Woloshuk, J. H. Nuijens, P. J. Krimpenfort, F. R. Pieper, H. A. de Boer, and R. Strijker (1994). Expression of human lactoferrin in milk of transgenic mice.Transgenic Res. 3:99–108.

    PubMed  Google Scholar 

  43. J. H. Nuijens, M. E. J. Geerts, P. H. C. van Berkel, P. P. Hartevelt, H. A. de Boer, H. A. van Veen, and F. R. Pieper (1995). Characterization of recombinant human lactoferrin expressed in the milk of transgenic mice.Proc. 2nd Int'l. Conf. on Structure and Function of LF.

  44. D. Legrand, V. Salmon, B. Coddeville, M. Benaissa, Y. Plancke, and G. Spik (1995). Structural determination of two N-linked glycans isolated from recombinant human lactoferrin expressed in BHK cells.FEBS Lett. 365:57–60.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Pharming BV, Leiden, The Netherlands

    Jan H. Nuijens

  2. Leiden Institute of Chemistry, Medical Biotechnology Department, Gorlaeus Laboratories, Leiden University, The Netherlands

    Patrick H. C. van Berkel

  3. Department of Animal Sciences, Laboratories of Molecular and Developmental Biology, Ohio Agricultural Research and Development Center, The Ohio State University, 1680 Madison Ave., 44691, Wooster, Ohio

    Floyd L. Schanbacher

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  1. Jan H. Nuijens
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  2. Patrick H. C. van Berkel
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  3. Floyd L. Schanbacher
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Additional information

Salary and support from state and federal funds to OARDC; Manuscript No. 49-96.

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Nuijens, J.H., van Berkel, P.H.C. & Schanbacher, F.L. Structure and biological actions of lactoferrin. J Mammary Gland Biol Neoplasia 1, 285–295 (1996). https://doi.org/10.1007/BF02018081

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