Quick viewing(Text Mode)

Biological Role of Lactoferrin

Biological Role of Lactoferrin

Archives ofDisease in Childhood 1992; 67: 657-661 657

REGULAR REVIEW Arch Dis Child: first published as 10.1136/adc.67.5.657 on 1 May 1992. Downloaded from

Biological role of

Lourdes Sanchez, Miguel Calvo, Jeremy H Brock

Lactoferrin is an -binding closely bearing in mind when considering its possible related in structure to the iron transport biological function. protein . Unlike transferrin, only contains 3-6-12-5 ,umol/l of traces are normally present in serum, and it is iron, and of this only 60-70% is in the whey instead found mainly in milk and other external fraction, the remainder being in the lipid secretions, and in the secondary granules of fraction (11-20%) or bound to casein (2-14%). " . Although lactoferrin was first iso- As a consequence, milk lactoferrin is only 6-8% lated 30 years ago, its biological role remains saturated with iron, presumably because of the unclear. Some aspects of its function were difficulty in gaining access to iron in the lipid discussed about 12 years ago in this journal,' fraction or casein micelles. and this review will attempt to reassess the function of lactoferrin in the light of the large amount of new information that has accrued Association of lactoferrin with other since then. molecules Knowledge of the structure of lactoferrin has Lactoferrin is very prone to binding to other been advanced by recent x ray crystallographic macromolecules. These include other milk studies, and the structure and iron binding such as IgA, casein, secretory compo- properties of lactoferrin are reviewed in detail nent, , , and f1-lactoglobulin.'2 elsewhere.2 Briefly lactoferrin, like transferrin, Lactoferrin also binds to DNA.'3 A report of reversibly binds two ferric , for which multiple forms of lactoferrin in human milk, synergistic binding of an anion, usually bicar- some of which exhibit activity,'4 bonate or carbonate, is necessary. However, its may arise from an interaction between lactoferrin

affinity constant for iron is 300 times greater and milk ribonuclease. Bovine milk ribonuclease http://adc.bmj.com/ than that of transferrin, and even in the is, like lysozyme, a small basic protein (mole- presence of a competing iron chelator such as cular weight 13 600),'5 and some ribonuclease citrate it can retain iron down to pH 3 or less activity in human milk was also associated with while transferrin loses it at pH 5. Unlike a molecule of this size. 14 So far no clear transferrin, lactoferrin is strongly basic. Human biological role has been established for this lactoferrin has been cloned and sequenced4 and propensity of lactoferrin to interact with other the recombinant protein expressed in baby proteins. hamster kidney cells.5 on September 28, 2021 by guest. Protected copyright. Biological functions of lactoferrin Lactoferrin in milk BACTERIOSTATIC ACTIVITY Human milk is particularly rich in lactoferrin, Almost all bacteria require iron for growth, and the concentration ranging from about 7 g/l in because of their iron sequestering properties, to about 1 g/l in mature milk, though the iron free (apo) forms of lactoferrin and it may rise again towards the end of lactation.6 7 transferrin are able to impede iron utilisation by A similar pattern is seen in the cow, but bacteria. A large number of studies, reviewed importantly the concentration in mid-lactation elsewhere,'6 have demonstrated a bacteriostatic Department of Food milk is very much lower, only about 0-1 g/l.8 effect and in some cases a bactericidal effect of Technology and Lactoferrin concentrations were normal in iron lactoferrin in vitro on a wide range of micro- Biochemistry, Veterinary Faculty, deficient mothers,9 but lower in mothers who organisms, including Gram positive and Gram University of Zaragoza, were generally malnourished,'0 which suggests negative bacteria, aerobes, anaerobes, and Spain that protein energy rather than . However, mechanisms other than simple Lourdes Sanchez Miguel Calvo iron influences lactoferrin synthesis in the iron withholding may be involved in the anti- University Department mammary gland. Although lactoferrin is found bacterial action of lactoferrin, such as blockade of Immunology, in the milk of some other species, it is completely of microbial carbohydrate '" or Western Infirmary, absent in others, such as the rat, rabbit, and destabilisation of the bacterial wall, perhaps Glasgow dog.6 The milk of the rat and rabbit do however through binding of calcium and magnesium.'8 Jeremy H Brock contain significant amounts of transferrin, but Lactoferrin may synergise with other anti- Correspondence and reprint requests to: the milk of the dog contains neither protein, bacterial proteins such as lysozyme, which is Dr Lourdes Sanchez, even though the iron content is exceptionally also present in milk. In this case even the iron Department of Immunology, Western Infirmary, high.6 The fact that lactoferrin is absent from saturated form is active, and inhibition results Glasgow Gll 6NT. the milk of some species is a point worth from agglutination by lactoferrin of bacteria 658 Sanchez, Calvo, Brock

whose cell wall has been modified by lysozyme. 19 unproved until the wealth of in vitro data can also enhance the bacteriostatic showing antimicrobial activity is supported by action of lactoferrin,20 probably by blocking convincing in vivo data, particularly from production or uptake of microbial . clinical trials. The possibility that lactoferrin Arch Dis Child: first published as 10.1136/adc.67.5.657 on 1 May 1992. Downloaded from Lactoferrin may also possess antiviral activity, might exert a systemic protective effect also as it could protect mice against polycythaemia deserves further investigation, as studies in due to Friend virus.2' This appears to be an mice have shown that lactoferrin has a protective indirect effect, perhaps via a reduction in target effect in experimental E coli septicaemia that is cell proliferation, and is probably related to the independent of its iron content.27 proposed inhibitory role of lactoferrin in myelopoiesis (see below). In vivo, lactoferrin in milk might exercise its ROLE OF LACTOFERRIN IN AND inhibitory effect on microbial growth in the THE mammary gland, in the intestine ofthe newborn, A number of studies suggest that lactoferrin or both. Its role as a defence against infection in may mediate some of the effects of inflammation the human mammary gland appears not to have and have a role in regulating various components been investigated, but in concentrations of the immune system. It was proposed some of lactoferrin increase during intramammary years ago that lactoferrin released by degranu- infection,22 suggesting a possible role as a lating neutrophils mediated the hyposideraemia mammary non-specific defence mechanism. of inflammation by removing iron from plasma Conditions in the bovine mammary gland im- transferrin and short circuiting it to mediately before parturition and during involu- of the reticuloendothelial system, where it was tion favour antimicrobial activity of lactoferrin incorporated into .28 However, iron as concentrations of are higher and uptake by macrophages from lactoferrin is at those of citrate lower than in milk.22 23 Thus best extremely slow,29 and there is no recycling lactoferrin might perform a role in preventing of the protein as occurs with transferrin, as infection of the mammary gland, particularly at lactoferrin that has bound to monocytes cannot parturition and involution. subsequently rebind to these cells.30 In addition, It has frequently been suggested that the the rate of exchange of iron between transferrin antimicrobial activity of lactoferrin plays a part and lactoferrin at physiological pH is likely to in the selection of the intestinal flora of the beextremely slow, and finallyneutrophil-derived newborn and preventing colonisation by entero- lactoferrin differs from milk lactoferrin, which pathogenic organisms. The conditions in the was used in most studies, in lacking the intestine ofthe newborn may be more favourable terminal fucose residues in its glycan chains that for lactoferrin than those in the lactating mam- are required for binding to macrophages.3' It mary gland, as citrate is rapidly absorbed and has also been found in mice that interleukin-1 intestinal fluid has a high concentration of induces hypoferraemia even in the presence of bicarbonate, although this function might be neutropenia,32 suggesting that lactoferrin is adversely affected by the proteolytic unimportant. Thus it now seems unlikely that http://adc.bmj.com/ present in the intestine, as discussed below. lactoferrin plays a significant part in the hypo- Nevertheless, despite the wealth of in vitro ferraemia of inflammation. data, attempts to establish an in vivo anti- Lactoferrin might also contribute to the microbial role for lactoferrin have generally bactericidal activity of neutrophils by two yielded disappointing results. The much quoted opposing mechanisms. In the apo form it may experimental study of Bullen et al,20 which perform an iron withholding function and suggested a protective effect of lactoferrin in prevent growth of phagocytosed bacteria.33 On on September 28, 2021 by guest. Protected copyright. newborn guinea pigs infected with Escherichia the other hand iron-lactoferrin may provide iron coli is open to other interpretations, as discussed that can catalyse the production of free radicals previously in this journal.' However, addition which lead to microbial killing within the of chicken ovotransferrin to cows' milk was able phagolysosome of phagocytic cells.34 The ability to reduce mortality and bacterial counts in of lactoferrin to promote formation of free young guinea pigs infected with enteropatho- radicals is probably confined to acidic conditions genic E coli.24 Two more recent clinical studies such as those within the phagolysosome, as at have analysed the faecal flora of infants fed physiological pH it is more likely that lactoferrin bovine lactoferrin (in one case in conjunction inhibits radical production by scavenging with bovine IgG) and failed to find any signifi- catalytic 'free' iron.35 A role for lactoferrin in cant difference between infants fed lactoferrin- the antimicrobial activity of neutrophils is supplemented formula and controls fed un- supported by the finding that patients whose supplemented formula.25 26 However, differ- neutrophils lack specific granules suffer from ences between bovine and human recurrent infections.36 (such as resistance to proteolysis, discussed Lactoferrin may also act as an inhibitor below) may mean that bovine lactoferrin is not of secretion of -monocyte-colony an appropriate substitute for the human protein, stimulating factor (GM-CSF).37 This complex and recombinant DNA technology now offers area has been intensively investigated and is the possibility of obtaining sufficient human reviewed fully elsewhere.38 In summary, lacto- lactoferrin for clinical trials. ferrin appears to act by decreasing synthesis of Thus although it is now well established that interleukin-l which is necessary for GM-CSF breast feeding offers protection to the newborn production. Iron-lactoferrin was more effective infant against gastrointestinal infection, the part than apo lactoferrin but it is not known what if played by lactoferrin must still be considered any part is played by iron. Lactoferrin isolated Biological role oflactofemrn 659

from neutrophils lacking receptors for the Fc ing characteristics of these proteins differ region of immunoglobulin or from neutrophils between species. However, there is so far no of leukaemia patients was inactive, though the evidence that these membrane proteins actually reason for this is unclear as possible differences mediate uptake or transport oflactoferrin-bound Arch Dis Child: first published as 10.1136/adc.67.5.657 on 1 May 1992. Downloaded from between the active and inactive forms of lacto- iron in mucosal cells. Given that there are also ferrin were not investigated. studies suggesting that lactoferrin may inhibit The role of lactoferrin as an inhibitor of iron absorption, reviewed previously,' our myelopoiesis is somewhat controversial, how- earlier conclusion that lactoferrin controls ever, as some reports have failed to find any rather than promotes iron absorption in the inhibitory effect.39 40 Some aspects of the neonate still seems to be valid. original studies such as the extremely low concentrations oflactoferrin required for activity (10-'7 M) and a discrepancy between the PROTEOLYTIC DEGRADATION OF LACTOFERRIN of the active component (6-5)37 AND SURVIVAL IN THE and purified lactoferrin (8 7)41 require explan- A role for lactoferrin in iron absorption or ation. Further work is needed, particularly with establishment of the microbial flora of the gut a view to establishing how lactoferrin itself presupposes a certain resistance to the conditions initiates these events at the molecular level, within the gastrointestinal tract. In vitro studies before its role in myelopoiesis can be regarded have found that apolactoferrin is more sensitive as fully established. to the action of than iron-lactoferrin, Lactoferrin has been reported to affect various although human apolactoferrin was less sensi- aspects ofthe immune system, such as inhibiting tive than bovine.60 Lactoferrin is also degraded in vitro synthesis,42 regulating mono- by gastric fluid from premature babies, though cyte/ cytotoxic activity,43 44 and unlike transferrin or casein more degradation affecting lymphocyte proliferation.458 In most occurred at pH 3-2 than at pH 18.6' However of these studies the mechanism by which the gastric pH will be raised by the buffering lactoferrin carries out these functions was not capacity of milk proteins, and the intestinal established. The effect on lymphocyte prolifer- flora and the velocity of transit also affect ation is unclear, as some authors have reported digestion of lactoferrin.9 Studies of lactoferrin enhancement45 and others inhibition.46 47 Pos- isolated from the faeces of newborn infants fed sibly this may depend upon culture conditions, cows' milk supplemented with human lacto- as recent work has suggested that apolactoferrin ferrin or bovine lactoferrin showed that iron- can overcome the inhibitory effect of 'free' iron lactoferrins survived better than the apo forms on lymphocyte proliferation, but itself inhibits and, surprisingly, bovine lactoferrin was more proliferation when iron is bound to transferrin.48 resistant than human.62 Partly digested proteins Activation of T lymphocytes induces the maintained their capacity to bind iron after presence of lactoferrin-binding molecules in the excretion, and fragments of human lactoferrin 49 to ,45 and binding to B cells has obtained by acid hydrolysis were still able http://adc.bmj.com/ also been reported.50 However, further work is bind to the putative rhesus monkey mucosal required before an immunoregulatory role for , albeit with lower affinity than intact lactoferrin can be clearly established. lactoferrin.63 Intact lactoferrin and fragments have been detected in the urine of premature infants ROLE OF LACTOFERRIN IN THE ABSORPTION OF receiving human milk,' arising apparently IRON from lactoferrin absorbed across the gut. '3 This The greater bioavailability of iron and higher suggests that lactoferrin is partially degraded in on September 28, 2021 by guest. Protected copyright. concentration of lactoferrin in human milk the gut and that significant absorption of this compared with cows' milk suggests that lacto- protein occurs in the premature infant. How- ferrin might promote iron absorption in breast ever, some fragments may be present before fed infants. In a previous review in this journal ingestion, as in contrast to a previous report65 it was suggested that lactoferrin actually had an we have recently found lactoferrin fragments in opposite effect, and served as an additional human and bovine milk.' It seems less likely control of iron absorption during the neonatal that lactoferrin absorption occurs in term period.' More recent clinical trials have failed to infants, as no difference in plasma lactoferrin demonstrate any improvement in iron absorp- concentrations was found between breast and tion in infants fed formula milk supplemented bottle fed infants.67 with (bovine) lactoferrin.5' 52 A study in rats did show that feeding lactoferrin improved iron status53 but the rat is a poor model for such ACTIVITY OF LACTOFERRIN AS A GROWTH FACTOR studies as the milk of this species does not Recent studies have suggested that lactoferrin contain lactoferrin. Studies in piglets,54 wean- may promote cell growth. As well as possibly ling mice,55 or infant rhesus monkeys56 showed promoting lymphocyte proliferation (see above), that the bioavailability of iron bound to lacto- human lactoferrin also stimulated growth of ferrin was no better than that of inorganic iron. various cell lines.29 68 It also enhanced prolifer- If lactoferrin were to have a role in iron ation of rat mucosal crypt cells,69 which sug- absorption one might expect a receptor to exist gests that it might play a part in maturation of in mucosal cells. Lactoferrin-binding proteins the intestine in the newborn. The possibility have been identified in the microvillus mem- that lactoferrin acts as a growth factor is branes of rabbit,57 mouse,58 and rhesus monkey supported by the presence ofhigh concentrations enterocytes.59 The molecular weights and bind- of lactoferrin in some tumours,70 although the 660 Sdnchez, Calvo, Brock

reasons for these high concentrations are the reticuloendothelial system or by biliary unclear. In some cases growth promotion re- excretion. Further studies, particularly of lacto- quired iron68 whereas in others iron was ferrin-cell interactions, may help to establish unimportant.29 69 The mechanism by which the validity of this proposal. Arch Dis Child: first published as 10.1136/adc.67.5.657 on 1 May 1992. Downloaded from lactoferrin is able to stimulate cell growth is therefore unclear, but seems unlikely to involve 1 Brock JH. Lactoferrin in human milk: its role in iron iron transport in an analogous manner to absorption and protection against enteric infection in the transferrin, as lactoferrin is not internalised and newborn infant. Arch Dis Child 1980;55:417-21. 2 Baker EN, Rumball SV, Anderson BF. : insights little or no iron is taken up from lactoferrin.29 It into structure and function from studies on lactoferrin. might involve activation of membrane oxido- Trends Biochem Sci 1987;12:350-3. 3 Anderson BF, Baker HM, Norris GE, DW, Baker EN. reductase activity.7' Structure of human lactoferrin: crystallographic structure analysis and refinement at 2-8A resolution. J Mol Biol 1989;209:71 1-34. 4 Powell MJ, Ogden JE. sequence of human Conclusion: the biological function of lactoferrin cDNA. Nucleic Acids Res 1990;18:4013. 5 Stowell KM, Rado TA, Funk WD, Tweedie JW. Expression lactoferrin-a unifying hypothesis of cloned human lactoferrin in baby-hamster kidney cells. Over the past 10 years there has been consider- Biochem J 1991;276:349-55. 6 Masson PL, Heremans JF. Lactoferrin in milk from different able research on the function of lactoferrin, species. Comp Biochem Physiol 1971;39B: 119-29. much of it in areas unrelated to the traditional 7 Hennart PF, Brasseur DJ, Delogne-Desnoeck JB, Dramaix MM, Robyn CE. Lysozyme, lactoferrin, and secretory fields of iron absorption and antimicrobial immunoglobulin A content in : influence of activity. Despite this, no clear biological role for duration of lactation, nutrition status, prolactin status, and parity of mother. Am J Clin Nutr 1991;53:32-9. lactoferrin has been established. Its anti- 8 Sanchez L, Aranda P, Perez MD, Calvo M. Concentration of microbial activity, so well documented in vitro, lactoferrin and transferrin throughout lactation in cow's colostrum and milk. Biol Chem Hoppe Seyler 1988;369: still awaits convincing in vivo evidence. New 1005-8. studies of iron absorption have generally failed 9 Prentice A, McCarthy A, Stirling DM, Vasquez-Velasquez L, Ceesay SM. Breast milk IgA and lactoferrin survival in to show that iron in lactoferrin has a higher the gastrointestinal tract-a study in ruralGambian children. bioavailability than iron salts, and there is still Acta Paediatr Scand 1989;78:505-12. 10 Houghton MR, Gracey M, Burke V, Botrell C, Spargo RM. no direct evidence that lactoferrin actually Breast milk lactoferrin levels in relation to maternal mediates uptake across the mucosa. Although nutritional status. J Pediatr Gastroenterol Nutr 1985;4: 230-3. lactoferrin-binding proteins have been identified 11 Lonnerdal B. Iron in human milk and cow's milk-effects of in mucosal membranes, these could just as binding on bioavailability. In: Lonnerdal B, ed. Iron metabolism in infants. Boca Rat6n, Florida: CRC Press, easily serve to regulate iron transport as enhance 1990:87-108. it. A role in hypoferraemia now seems unlikely, 12 Lampreave F, Pineiro A, Brock JH, Castillo H, Sanchez L, Calvo M. Interaction of bovine lactoferrin with other and effects on myelopoiesis and the immune proteins of milk whey. International journal of Biological system are either controversial or essentially Macromolecules 1990;12:2-5. 13 Hutchens TW, Henry JF, Yip T-T, et al. Origin of intact phenomenological, with little information on lactoferrin and its DNA-binding fragments found in the how lactoferrin actually mediates these effects. urine of human milk-fed premature infants. Evaluation by stable isotopic enrichment. Pediatr Res 1991;29:243-50. Although lactoferrin receptors or binding 14 Furmanski P, Li Z-P, Fortuna MB, Swamy CVB, Das MR. proteins have been reported from a wide variety Multiple molecular forms of human lactoferrin. Identifi- of cells and tissues the molecular structure and cation of a class of lactoferrins that possess ribonuclease http://adc.bmj.com/ activity and lack iron-binding capacity. J Exp Med 1989; binding characteristics of these putative recep- 170:415-29. 15 Bingham EW, Zittle CA. Ribonuclease of bovine milk: tors varies considerably, and in many cases purification and properties. Arch Biochem Biophys 1964; binding is relatively non-specific. It may well be 106:235-9. 16 Weinberg ED. Iron withholding: a defense against infection that the various apparently unrelated effects of and neoplasia. Physiol Rev 1984;64:65-102. lactoferrin on the immune system arise from its 17 Arnold RR, Russell JE, Champion WJ, Brewer M, Gauthier JJ. Bacterial activity of human lactoferrin: differentiation ability to bind to macrophages and lymphocytes. from the stasis of iron deprivation. Infect Immun 1982;35: This could alter the surface charge of the cell 792-9. on September 28, 2021 by guest. Protected copyright. 18 Ellison RT, Laforce FM, Giehl TJ, Boose DS, Dunn BE. membrane, with consequent effects on the Lactoferrin and transferrin damage of the Gram-negative various cell-cell interactions that have a crucial outer membrane is modulated by Ca2" and Mg2". J Gen Microbiol 1990;136:1437-46. role in many immunological mechanisms. 19 Suzuki T, Yamauchi K, Kawase K, Tomita M, Kiyosawa I, We believe that current evidence suggests Okonogi S. Collaborative bacteriostatic activity of bovine lactoferrin with lysozyme against Escherichia coli 0111. that lactoferrin, despite its structural similarity Agricultural and Biological Chemistry 1989;53:1705-6. to transferrin, does not act as an iron transport 20 Bullen JJ, Rogers HJ, Leigh L. Iron-binding proteins in milk and resistance to Escherichia coli infection in infants. BMJ protein. Instead, we propose that its role is that 1972;i:69-75. ofa specialised iron-scavenging protein, designed 21 Lu L, Hangoc G, Oliff A, Chen LT, Shen R-N, Broxmeyer HE. Protective influence of lactoferrin on mice infected to act particularly under conditions where with the polycythemia-inducing of Friend virus transferrin would be less effective at binding complex. Cancer Res 1987;47:4184-8. 22 Nonnecke BJ, Smith KL. Biochemical and antibacterial iron due to reduced pH, such as exist in the properties of bovine mammary secretion during mammary gastrointestinal tract or inflammatory lesions. involution and at parturition. J Dairy Sci 1984;67:2863-72. 23 Erhardt G, Senft B. Veranderungen in der bakteriostatischen By binding iron under these conditions it would aktivitat de lactoferrins wahrend der laktation sowie nach render harmless 'free' iron that might otherwise experimenteller infektion der milchdruse mit Staphylococ- cus aureus. Zentralbl Veterinarmed [Al 1982;29:405-19. cause free radical-mediated damage to sensitive 24 Antonini E, Orsi N, Valenti P. Effetto delle transferrine sulla tissues, reduce absorption of unwanted iron in patogenicita delle enterobacteriaceae. Giormale di Malattie Infettive e Parassitarie (Milano) 1977;29:481-9. the immediate postnatal period, and decrease its 25 Balmer SE, Scott PH, Wharton BA. Diet and faecal flora in availability to micro-organisms. The ability of the newborn. Arch Dis Child 19899-641685-90. 26 Moreau MC, Duval-Ifiah Y, Muller MC, et al. Effet de la lactoferrin to bind to a wide variety of cells and lactoferrine bovine et des IgG bovines donnes per os sur tissues, perhaps without the need for expression l'implantation de Escherichia coli dana le tube digestif de souris gnotoxeniques et de nouveau-nes humains. Annales of a truly specific receptor, would enhance its de Microbiologie (Institut Pasteur) 1983;134B:429-41. ability to prevent free radical-mediated damage 27 Zagulski T, Lipinski P, Zagulska A, Broniek 5, Jarzabek Z. Lactoferrin can protect mice against a lethal dose of or microbial invasion. It would also help to Escherichia coli in experimental infection in vivo. British ensure its eventual removal and catabolism via lournal of Experimental Pathology 1989;70:697-704. Biological role oflactoferrin 661

28 Van Snick JL, Masson PL, Heremans JF. The involvement The N-terminal domain of human lactotransferrin binds of lactoferrin in the hyposideremia of inflammation. J Exp specifically to -stimulated peripheral Med 1974;140:1068-84. blood human lymphocyte receptors. FEBS Lett 1989;255: 29 Oria R, Alvarez-Hernandez X, Liceaga J, Brock JH. Uptake 201-4.

and handling of iron from transferrin, lactoferrin and 50 Butler TW, Grossi CE, Canessa A, Pistoia V, Barton JC. Arch Dis Child: first published as 10.1136/adc.67.5.657 on 1 May 1992. Downloaded from immune complexes by a macrophage cell line. Biochem J Immunoreactive lactoferrin in resting, activated and neo- 1988;252:22 1-5. plastic lymphocytes. Leuk Res 1990;14:441-7. 30 Birgens HS, Kristensen L0. Impaired receptor binding and 51 Fairweather-Tait SJ, Balmer SE, Scott PH, Minski MJ. decrease in isoelectric point of lactoferrin after interaction Lactoferrin and iron absorption in newborn infants. Pediatr with human monocytes. EurJ7 Haematol 1990;45:31-5. Res 1987;22:651-4. 31 Derisbourg P, Wieruszeski JM, Montreuil J, Spik G. 52 Schulz-Lell G, Dorner K, Oldigs HG, Sievers E, Schaub J. Primary structure of glycans isolated from human leucocyte Iron availability from an supplemented with lactotransferrin. Absence of fucose residues questions the bovine lactoferrin. Acta Paediatr Scand 1991;80:155-8. proposed mechanism of hyposideraemia. Biochem J 1990; 53 Kawakami H, Hiratsuka M, Dosako S. Effects of iron- 269:821-5. saturated lactoferrin on iron absorption. Agricultural and 32 Gordeuk VR, Prithviraj P, Dolinar T, Brittenham GM. Biological Chemistry 1988;52:903-8. Interleukin 1 administration in mice produces hypoferremia 54 Fransson GB, Thoren-Tolling K, Jones B, Hambraeus L, despite neutropenia. J Clin Invest 1988;82:1934-8. Lonnerdal B. Absorption of lactoferrin iron in suckling 33 Bullen JJ, Armstrong JA. The role of lactoferrin in the pigs. Nutrition Research 1983;3:373-84. bactericidal function of polymorphonuclear leucocytes. 55 Fransson GB, Keen CL, Lonnerdal B. Supplementation of Immunology 1979;36:781-91. milk with iron bound to lactoferrin using weanling mice. I. 34 Lima MF, Kierszenbaum F. Lactoferrin effects on phagocytic Effects on hematology and tissue iron.J Pediatr Gastrenterol cell function. II. The presence of iron is required for the Nutr 1983;2:693-700. lactoferrin molecule to stimulate intracellular killing by 56 Davidson LA, Litov RE, Lonnerdal B. Iron retention from macrophages but not to enhance uptake of particles and lactoferrin-supplemented formulas in infant rhesus microorganisms. J Immunol 1987;139:1647-51. monkeys. Pediatr Res 1990;27:170-80. 35 Aruoma0l, Halliwell B. Superoxide-dependentandascorbate- 57 Mazurier J, Montreuil J, Spik G. Visualization of lacto- dependent formation of hydroxyl radicals from hydrogen transferrin brush-border receptors by blotting. peroxide in the presence of iron. Are lactoferrin and Biochim Biophys Acta 1985;821:453-60. transferrin promoters of hydroxyl-radical generation? 58 Hu WL, Mazurier J, Montreuil J, Spik G. Isolation and Biochem J 1987;241:273-8. partial charactensation of a lactotransferrin receptor from 36 Breton-Gorius J, Mason DY, Buriot D, Vilde JL, Griscelli C. mouse intestinal brush border. Biochemistry 1990;29: Lactoferrin deficiency as a consequence of a lack of specific 535-41. granules in neutrophils from a patient with recurrent 59 Davidson LA, Lonnerdal B. Specific binding of lactoferrin to infections. Am J7 Pathol 1980;99:413-9. brush border membrane: ontogeny and effect of glycan 37 Broxmeyer HE, Smithyman A, Eger RR, Meyers PA, De chain. Am J Physiol 1988;254:G580-5. Sousa M. Identification of lactoferrin as the granulocyte- 60 Brines RD, Brock JH. The effect of trypsin and chymotrypsin derived inhibitor of colony-stimulating activity production. on the in vitro antimicrobial and iron-binding properties of J Exp Med 1978;148:1052-67. lactoferrin in human milk and bovine colostrum. Biochim 38 Broxmeyer HE. Iron-binding proteins and the regulation of Biophys Acta 1983;759:229-35. hematopoietic cell proliferation/differentiation. In: De 61 Britton JR, Koldovsky 0. Gastric luminal digestion of Sousa M, Brock JH, eds. Iron in immunity, cancer and lactoferrin and transferrin by preterm infants. Early Hum inflammation. Chichester: John Wiley, 1989:199-221. Dev 1989;19:127-35. 39 Winton EF, Kinkade JM, Vogler WR, Parker MB. In vitro 62 Spik G, Brunet B, Mazurier-Dehaine C, Fontaine G, studies of lactoferrin and murine granulopoiesis. Blood Montreuil J. Characterization and properties of the human 1981;57:574-8. and bovine lactotransferrins extracted from the faeces of 40 Stryckmans P, Delforge A, Amson RB, et al. Lactoferrin: no newborn infants. Acta Paediatr Scand 1982;71:979-85. evidence for its role in regulation of CSA production by 63 Davidson LA, Lonnerdal B. Fe-saturation and proteolysis of human lymphocytes and monocytes. Blood Cells 1984;10: human lactoferrin: effecton brush-border receptor-mediated 369-95. uptake of Fe and Mn. Am J Physiol .1989;257:G930-4. 41 Moguilevsky N, Retegui LA, Masson PL. Comparison of 64 Hutchens TW, Henry JF, Yip T-T. Structurally intact (78- human lactoferrins from milk and neutrophilic leucocytes. kDa) forms of maternal lactoferrin purified from urine of Biochem J 1985;229:353-9. preterm infants fed human milk. Identification of a trypsin- 42 Duncan RL, McArthurWP. Lactoferrin-mediated modulation like proteolytic cleavage event in vivo that does not result in of mononuclear cell activities. I. Suppression of the murine fragment dissociation. Proc NatI Acad Sci USA 1991;88: in vitro primary antibody response. Cell Immunol 1981;63: 2994-8.

308-20. 65 Goldman AS, Garza C, Schanler RJ, Goldblum RM. Mole- http://adc.bmj.com/ 43 McCormick JA, Markey GM, Morris TCM. Lactoferrin- cular forms of lactoferrin in stool and urine from infants fed inducible monocyte cytotoxicity for K562 cells and decay of human milk. Pediatr Res 1990;27:252-5. natural killer lymphocyte cytotoxicity. Clin Exp Immunol 66 Calvo M, Mata L, Sanchez C, et al. Autoassociation of 1991 ;83: 154-6. lactoferrin proteolytic fragments from human and bovine 44 Nishiya K, Horwitz DA. Contrasting effects of lactoferrin on milk. Proceedings of the 10th International Conference on human lymphocyte and monocyte natural killer activity and Iron and Iron Proteins. Oxford, 1991:absP29. antibody-dependent cell-mediated cytotoxicity. J Immunol 67 Scott PH. immunoassay of lactoferrin in newborn 1982;129:25 19-23. term infants: reference values and influence of diet. Ann 45 Mazurier J, Legrand D, Hu WL, Montreuil J, Spik G. Clin Biochem 1989;26:407-1 1. Expression of human lactotransferrin receptors in phyto- 68 Azuma N, Mori H, Kaminogawa S, Yamauchi K. Stimulatory

haemagglutinin-stimulated human peripheral blood effect of human lactoferrin on DNA synthesis in BALB/c on September 28, 2021 by guest. Protected copyright. lymphocytes. Isolation of the receptors by antiligand- 3T3 cells. Agricultural and Biological Chemistry 1989;53: . EurJ7 Biochem 1989;179:481-7. 31-5. 46 Richie ER, Hiliard JK, Gilmore R, Gillespie DJ. Human 69 Nichols BL, McKee KS, Huebers HA. Iron is not required in milk-derived lactoferrin inhibits mitogen and alloantigen the lactoferrin stimulation of thymidine incorporation into induced human lymphocyte proliferation. J Reprod the DNA of rat crypt enterocytes. Pediatr Res 1990;27: Immunol 1987;12:137-48. 525-8. 47 Slater K, Fletcher J. Lactoferrin derived from neutrophils 70 Tuccari G, Barresi G, Arena F. Inferrera C. Immunocyto- inhibits the mixed lymphocyte reaction. Blood 1987;69: chemical detection of lactoferrin in human gastric carcino- 1328-33. mas and adenomas. Arch Pathol Lab Med 1989;113:912-3. 48 Djeha A, Brock JH. Effect of transferrin, lactoferrin and 71 Sun IL, Crane FL, Morre DJ. Low H, Faulk WP. chelated iron on human T-lymphocytes. Br J Haematol Lactoferrin activates plasma membrane oxidase and Na+/H + 1992 (in press). antiport activity. Biochem Biophys Res Commun 1991;176: 49 Rochard E, Legrand D, Mazurier J, Montreuil J, Spik G. 498-504.

Top View