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PubMed2000

Lactoferrin is responsible for the fungistatic effect of human milk.

Human milk has recognized anti-microbial effects and it has been repeatedly shown that breast-fed infants have fewer and less severe infections than formula-fed infants. While most studies have focused on anti-bacterial and anti-viral activities few have focused on the anti-fungal effect of human milk. Dermal and other infections caused by fungi are common in very low birth weight (VLBW) infants. Using a liquid culturing method and Candida albicans and Rhodotorula rubra as representative fungi, we studied the anti-fungal effect of human milk and certain human milk proteins. In vitro, human milk showed potent inhibitory effect on fungal growth. Most, if not all of this effect was caused by lactoferrin via its iron-binding capacity; increasing the iron content of the incubation medium abolished the inhibitory effect. In contrast, other human milk proteins with known or suggested anti-microbial effects rather increased fungal growth. Viability test and electron microscopy revealed that the growth inhibitory effect of human milk, i.e. mediated by lactoferrin, is fungistatic rather than fungicidal.

Antifungal Agents↗
PubMed1992

Anion binding by human lactoferrin: results from crystallographic and physicochemical studies.

The anion-binding properties of lactoferrin (Lf), with Fe3+ or Cu2+ as the associated metal ion, have been investigated by physicochemical and crystallographic techniques. These highlight differences between the two sites and in the anion-binding behavior when different metals are bound. Carbonate, oxalate, and hybrid carbonate-oxalate complexes have been prepared and their characteristic electronic and EPR spectra recorded. Oxalate can displace carbonate from either one or both anion sites of Cu2(CO3)2Lf, depending on the oxalate concentration, but no such displacement occurs for Fe2(CO3)2Lf. Addition of oxalate and the appropriate metal ion to apoLf under carbonate-free conditions gives dioxalate complexes with both Fe3+ and Cu2+, except when traces of EDTA remain associated with the protein, when hybrid complexes M2(CO3)(C2O4)Lf can result. The anion sites in the crystal structures of Fe2(CO3)2Lf, Cu2-(CO3)2Lf, and Cu2(CO3)(C2O4)Lf, refined at 2.2, 2.1, and 2.2 A, respectively, have been compared. In every case, the anion is hydrogen bonded to the N-terminus of helix 5, an associated arginine side chain, and a nearby threonine side chain. The carbonate ion binds in bidentate fashion to the metal, except in the N-lobe site of dicupric lactoferrin, where it is monodentate; the difference arises from slight movement of the metal ion. The hybrid complex shows that the oxalate ion binds preferentially in the C-lobe site, in 1,2-bidentate mode, but with the displacement of several nearby side chains. These observations lead to a generalized model for synergistic anion binding by transferrins.

Binding, Competitive↗
PubMed2005

Composition of pH-sensitive triad in C-lobe of human serum transferrin. Comparison to sequences of ovotransferrin and lactoferrin provides insight into functional differences in iron release.

The transferrins (TF) are a family of bilobal glycoproteins that tightly bind ferric iron. Each of the homologous N- and C-lobes contains a single iron-binding site situated in a deep cleft. Human serum transferrin (hTF) serves as the iron transport protein in the blood; circulating transferrin binds to receptors on the cell surface, and the complex is internalized by endocytosis. Within the cell, a reduction in pH leads to iron release from hTF in a receptor-dependent process resulting in a large conformational change in each lobe. In the hTF N-lobe, two critical lysines facilitate this pH-dependent conformational change allowing entry of a chelator to capture the iron. In the C-lobe, the lysine pair is replaced by a triad of residues: Lys534, Arg632, and Asp634. Previous studies show that mutation of any of these triad residues to alanine results in significant retardation of iron release at both pH 7.4 and pH 5.6. In the present work, the role of the three residues is probed further by conversion to the residues observed at the equivalent positions in ovotransferrin (Q-K-L) and human lactoferrin (K-N-N) as well as a triad with an interchanged lysine and arginine (K534R/R632K). As expected, all of the constructs bind iron and associate with the receptor with nearly the same K(D) as the wild-type monoferric hTF control. However, interesting differences in the effect of the substitutions on the iron release rate in the presence and absence of the receptor at pH 5.6 are observed. Additionally, titration with KCl indicates that position 632 must have a positively charged residue to elicit a robust rate acceleration as a function of increasing salt. On the basis of these observations, a model for iron release from the hTF C-lobe is proposed. These studies provide insight into the importance of charge and geometry of the amino acids at these positions as a partial explanation for differences in behavior of individual TF family members, human serum transferrin, ovotransferrin, and lactoferrin. The studies collectively highlight important features common to both the N- and C-lobes of TF and the critical role of the receptor in iron release.

Amino Acid Sequence↗
PubMedDate not supplied

Recovery of lactoferrin and lactoperoxidase from sweet whey using colloidal gas aphrons (CGAs) generated from an anionic surfactant, AOT.

The recovery of lactoferrin and lactoperoxidase from sweet whey was studied using colloidal gas aphrons (CGAs), which are surfactant-stabilized microbubbles (10-100 microm). CGAs are generated by intense stirring (8000 rpm for 10 min) of the anionic surfactant AOT (sodium bis-2-ethylhexyl sulfosuccinate). A volume of CGAs (10-30 mL) is mixed with a given volume of whey (1-10 mL), and the mixture is allowed to separate into two phases: the aphron (top) phase and the liquid (bottom) phase. Each of the phases is analyzed by SDS-PAGE and surfactant colorimetric assay. A statistical experimental design has been developed to assess the effect of different process parameters including pH, ionic strength, the concentration of surfactant in the CGAs generating solution, the volume of CGAs and the volume of whey on separation efficiency. As expected pH, ionic strength and the volume of whey (i.e. the amount of total protein in the starting material) are the main factors influencing the partitioning of the Lf.Lp fraction into the aphron phase. Moreover, it has been demonstrated that best separation performance was achieved at pH = 4 and ionic strength = 0.1 mol/L i.e., with conditions favoring electrostatic interactions between target proteins and CGAs (recovery was 90% and the concentration of lactoferrin and lactoperoxidase in the aphron phase was 25 times higher than that in the liquid phase), whereas conditions favoring hydrophobic interactions (pH close to pI and high ionic strength) led to lower performance. However, under these conditions, as confirmed by zeta potential measurements, the adsorption of both target proteins and contaminant proteins is favored. Thus, low selectivity is achieved at all of the studied conditions. These results confirm the initial hypothesis that CGAs act as ion exchangers and that the selectivity of the process can be manipulated by changing main operating parameters such as type of surfactant, pH and ionic strength.

Animals↗
PubMed1998

Metal complexes of bovine lactoferrin inhibit in vitro replication of herpes simplex virus type 1 and 2.

The inhibitory effect of bovine lactoferrin (BLf) saturated with ferric, manganese or zinc ions, on the infection of Vero cells by human herpes simplex virus type 1 (HSV1) and 2 (HSV2) was investigated. Viral infectivity determined by intracellular antigen synthesis and plaque formation was efficiently inhibited by metal saturated lactoferrins in a dose-dependent manner. Effective BLf concentrations which reduced the infection by 50% ranged from 5.2 to 31 micrograms ml-1 and were far below the cytotoxicity threshold. Fe3+BLf and Mn2+BLf exhibited selectivity indexes higher than Zn2+BLf and apoBLf for both viruses and the effect was mainly directed towards the early steps of infection. The slight viral inhibition shown by the citrate complexes of the different metals could indicate that the antiviral effect was not significantly influenced by Fe3+, Mn2+ or Zn2+ ions delivered by BLf into the cells.

Animals↗
PubMed2003

Effect of infusing lactoferrin hydrolysate into bovine mammary glands with subclinical mastitis.

The therapeutic effect of administering lactoferrin hydrolysate (LFH) into the mammary glands of cows with subclinical mastitis was evaluated. Seven millilitres of a preparation of LFH (7% protein) was infused into 35 quarters of 25 cows with subclinical mastitis. The numbers of bacteria in the milk from infected quarters decreased, and bacteria disappeared by the 14th day after the administration of LFH. The mean somatic cell counts (SCC) peaked one day after administration of LFH and the counts were significantly p < 0.01) decreased on days 7, 14 and 21 compared to those before the administration of LFH. The mean lactoferrin concentration in the milk peaked on days 2 or 3 and then gradually decreased to day 14, returning to the level before the administration of LFH. It appears that administration of LFH may have a therapeutic effect when infused into the quarters of cows with subclinical mastitis.

Animals↗
PubMed2004

Lactoferrin: role in iron homeostasis and host defense against microbial infection.

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.

Animals↗
PubMed2004

Neonatal small bowel epithelia: enhancing anti-bacterial defense with lactoferrin and Lactobacillus GG.

BACKGROUND AND AIMS: Extremely preterm human infants have increased susceptibility to small bowel infection. We hypothesized that early colonization of the immature small intestine with Lactobacillus GG (LGG), and use of a recombinant lactoferrin (rhLF) to promote growth of LGG, would enhance gut defenses against enteroinvasive Escherichia coli. METHODS: Newborn rat pups were treated with nothing, intra-gastric LGG, or rhLF + LGG on days 3 and 4 of life. Gut colonization by LGG was quantified in lavaged jejunal and ileal fluid and gut wall homogenates on day 5 of life. Separate studies used similarly treated litters of newborn rats that were infected late on day 4 of life with E. coli [10(12) CFU/kg]. Sixteen hours later, the numbers of E. coli were measured in small bowel fluid and gut wall homogenates. RESULTS: Control pups initially had lactic acid bacteria colonize the bowel, but these bacteria were not LGG. Pups treated with LGG or rhLF + LGG had significantly higher numbers of LGG in the ileum versus jejunum. Contrary to our hypothesis, rhLF did not augment LGG colonization. After E. coli-related gut infection, planktonic [lavage fluid] and epithelia-adherent growth [gut wall homogenates] of E. coli in the small bowel were most effectively reduced by pre-treatment with rhLF and LGG (P < .05). CONCLUSION: Prophylactic therapy with recombinant human lactoferrin and the probiotic, Lactobacillus GG, act to enhance defenses against invasive E. coli in the nascent small intestine. We suggest that rhLF and LGG are therapeutic agents that may reduce necrotizing enterocolitis and gut-related sepsis in preterm human infants.

Animals↗
PubMed2004

Safety of milk and milk derivatives in relation to BSE: the lactoferrin example.

Bovine Spongiform Encephalopathy (BSE) belongs to Transmissible Spongiform Encephalopathies (TSEs) or Prion diseases. BSE is a feed borne infection of cattle. Epidemiological and laboratory data suggest that the BSE infectious agent is responsible for the variant form of Creutzfeldt-Jakob Disease (vCJD) and that the oral route is the most plausible way of infection. Therefore there is concern that the BSE agent can be transmitted to humans by biological materials (i.e. meat products, blood, milk) from susceptible BSE animal species (mostly cows but possibly, sheep and goats). Lactoferrin (LF) can be produced by purification from large volumes of cow's milk or whey. Therefore, a potential BSE risk for milk and milk products needs to be evaluated by risk assessment. The Committee for proprietary Medicinal Products--CPMP of the European Commission and the WHO have categorized risk tissues from TSE susceptible ruminant species in different classes in relation to the BSE risk for medicinal products. Milk, colostrum, and tissues of the mammary gland have been classified in the category of no detectable infectivity. A secondary contamination of milk can be virtually excluded (i.e. milk is taken from living animals). In the light of current scientific knowledge and irrespective of the geographical origin, milk and milk derivatives (e.g. lactoferrin, lactose) are unlikely to present any risk of TSE contamination provided that milk is sourced from healthy animals in the same conditions as milk collected from human consumption. So the risk of milk and milk derivatives in relation to BSE is negligible.

Animals↗
PubMed2005

Technology insight: calprotectin, lactoferrin and nitric oxide as novel markers of inflammatory bowel disease.

Distinguishing patients with inflammatory bowel disease from those with irritable bowel syndrome can be difficult. A simple and reliable test that detects intestinal inflammation would therefore be very useful in the clinic. If such a test parameter correlated with the intensity of the inflammatory reaction it could also be used to monitor disease activity. Calprotectin, lactoferrin and nitric oxide are produced and released locally in much greater quantities in the inflamed gut than in the noninflamed gut. These compounds can be readily measured in fecal samples (calprotectin and lactoferrin) or directly in the intestinal lumen (nitric oxide gas). Here, we discuss what is known about these markers, how they could be used in clinical practice and how they can complement existing techniques used for the diagnosis and monitoring of inflammatory bowel disease.

Biomarkers↗
PubMed1976

Iron-dependent binding of 8-anilinonaphthalene-1-sulphonate by both lactoferrin and transferrin.

Fluorescence of 8-anilinonaphthalene-1-sulphonate is enhanced by both lactoferrin and transferrin. The enhancement is relatively low between pH 4 and 8, and high at below pH 4. At physiological pH the fluorescence enhancement is higher with the iron-deprived than with the iron-saturated proteins. Binding of iron by lactoferrin is associated with lowering affinity for the dye.

Anilino Naphthalenesulfonates↗
PubMed1985

Comparison of human lactoferrins from milk and neutrophilic leucocytes. Relative molecular mass, isoelectric point, iron-binding properties and uptake by the liver.

Human lactoferrins isolated from neutrophilic leucocytes and milk by CM-Sephadex chromatography were similar in Mr (76000) and pI (8.7). Upon acidification, both proteins released their two Fe3+ ions/molecule in a similar biphasic way. Both proteins intravenously injected into mice were cleared from plasma at the same rate. The maximal uptakes by the liver, which occurred 5 min after injection, were inhibited to the same extent by milk lactoferrin used as a competitor.

Animals↗
PubMed1987

Superoxide-dependent and ascorbate-dependent formation of hydroxyl radicals from hydrogen peroxide in the presence of iron. Are lactoferrin and transferrin promoters of hydroxyl-radical generation?

Apo-lactoferrin and apo-transferrin protect against iron-ion-dependent hydroxyl-radical (.OH) generation from H2O2 in the presence of superoxide radicals or ascorbic acid at pH 7.4, whether the necessary iron is added as ionic iron or as ferritin. Iron-loaded transferrin and lactoferrin [2 mol of Fe(III)/mol] show no protective ability, but do not themselves accelerate .OH production unless chelating agents are present in the reaction mixture, especially if the proteins are incorrectly loaded with iron. At acidic pH values, the protective ability of the apoproteins is diminished, and the fully iron-loaded proteins can release some iron in a form able to accelerate .OH generation. The physiological significance of these observations is discussed.

Apoproteins↗
PubMed1997

The N-terminal Arg2, Arg3 and Arg4 of human lactoferrin interact with sulphated molecules but not with the receptor present on Jurkat human lymphoblastic T-cells.

We previously characterized a 105 kDa receptor for human lactoferrin (hLf) on Jurkat human lymphoblastic T-cells. To delineate the role of the basic cluster Arg2-Arg3-Arg4-Arg5 of hLf in the interaction with Jurkat cells, we isolated N-terminally deleted hLf species of molecular mass 80 kDa lacking two, three or four N-terminal residues (hLf-2N, hLf-3N and hLf-4N) from native hLf that had been treated with trypsin. Native hLf bound to 102000 sites on Jurkat cells with a dissociation constant (Kd) of 70 nM. Consecutive removal of N-terminal arginine residues from hLf progressively increased the binding affinity but decreased the number of binding sites on the cells. A recombinant hLF mutant lacking the first five N-terminal residues (rhLf-5N) bound to 17000 sites with a Kd of 12 nM. The binding parameters of bovine lactoferrin (Lf) and native hLf did not significantly differ, whereas the binding parameters of murine Lf (8000 sites; Kd 30 nM) resembled those of rhLf-5N. Culture of Jurkat cells in the presence of chlorate, which inhibits sulphation, decreased the number of binding sites for both native hLf and hLf-3N but not for rhLf-5N, indicating that the hLf-binding sites include sulphated molecules. We propose that the interaction of hLf with a large number of binding sites (approx. 80000 per cell) on Jurkat cells is dependent on Arg2-Arg3-Arg4, but not on Arg5. Interaction with approx. 20000 binding sites per cell, presumably the hLf receptor, does not require the first N-terminal basic cluster of hLf. Moreover, the affinity of hLf for the latter binding site is enhanced approx. 6-fold after removal of the first basic cluster. Thus N-terminal proteolysis of hLf in vivo might serve to modulate the nature of its binding to cells and thereby its effects on cellular physiology.

Amino Acid Sequence↗
PubMed2002

Disposition kinetics of lactoferrin in milk after intramammary administration.

Disposition kinetics of lactoferrin (Lf) purified from cheese whey was studied in the milk of Finnish Ayrshire cows after intramammary administration of 1 g of Lf into one udder quarter. Intramammary administration of 1 g of Lf increased Lf concentration in milk for several hours. Mean elimination half-life of Lf was 2.2 h and a mean maximum concentration of 6.3 g/L was reached between 1 and 4 h. After 8 h of administration, Lf concentrations in milk decreased to almost the same level as before the infusion. Forty-eight hours postinfusion, the mean Lf concentration was again higher than in the milk samples taken before the infusion of Lf, being on average 1.5 g/L. Lactoferrin caused some local tissue irritation in the udder quarter. Severity of the irritation reactions varied between cows. The udder quarters of primiparous cows reacted faster than those of multiparous cows, but irritation reactions decreased more rapidly in the older cows than in primiparous cows. The cows had no general signs such as fever or anorexia. The somatic cell count returned to baseline level 4 days after the administration.

Animals↗
PubMed1997

Activated human gamma delta T lymphocytes express functional lactoferrin receptors.

Lactoferrin (Lf), an iron-binding protein in milk, mucosal secretions and neutrophil granules has bactericidal properties and is a source of iron for breast-fed infants. In this paper the authors show that most in vivo activated lymphocytes, i.e. freshly isolated lymphocytes from first trimester human decidua, and most in vitro activated human blood lymphocytes, express lactoferrin receptors (Lf-R), while unstimulated blood lymphocytes do not. All major lymphocyte subsets, i.e. alpha beta T cells, gamma delta T cells, CD8+ T cells, CD4+ T cells, B cells and NK cells, express Lf-R after activation. The proportion of Lf-R expressing activated gamma delta T cells is significantly larger than that of activated alpha beta T cells. Lf-R and transferrin receptors (Tr-R/CD71) show the same kinetics of appearance on activated blood lymphocytes and are, to a large extent, expressed on the same cells. However, 35% of decidual lymphocytes and 15% of activated blood lymphocytes express Lf-R only. Addition of Lf to cultures containing an optimal concentration of Tr augments the proliferative response to polyclonal T cell activators and alloantigens, suggesting that presently used standard culture conditions for in vitro activation are suboptimal in particular for gamma delta T cells. Lf-R on decidual lymphocytes contain bound Lf, which probably is produced locally. The results suggest that Lf is a growth-supporting factor, especially important in local immune responses in the mucosa.

Cell Division↗
PubMed2003

Reconstitution of the cellular immune response by lactoferrin in cyclophosphamide-treated mice is correlated with renewal of T cell compartment.

Cyclophosphamide is an alkylating agent used to treat both malignant and non-malignant immune-mediated inflammatory disorders in humans. It is also known as a potent immunosuppressive drug in humans and experimental animals. The aim of this study was to evaluate the effects of oral administration of lactoferrin (LF) on cellular responses and reconstruction of the lymphocyte pool in mice treated with cyclophosphamide (CP). Twelve week-old CBA mice were given a single intraperitoneal (i.p.) dose of CP (400 mg/kg body weight), then were treated per os with seven doses of LF (1 mg/dose) on alternate days. We demonstrated that the magnitude of delayed type hypersensitivity to ovalbumin, strongly diminished by CP action, was reconstituted by LF. Oral LF treatment also resulted in partial recovery of Concanavalin A-induced splenocyte proliferation. Blood profile analysis revealed elevation of leukocytosis by LF in CP-treated mice (from 64.9 to 84.76% of the control value). LF also caused substantial restoration of the percentage of the lymphocyte population in circulating blood (from 43.4 to 60.2% of the control values). LF alone had no effect on the neutrophil/lymphocyte ratio in normal mice, however, the total number of leukocytes decreased by 23.25%. Furthermore, we showed that LF increased the cellularity of spleens isolated from CP-treated mice (from 53.2 to 78.8%) and the content of peritoneal and alveolar macrophages (elevations from 50.6 to 67.3% and from 65.2 to 83.6%, respectively). Lastly, using panning technique, we demonstrated that LF strongly elevated the pool of CD3+ T cells in normal and CP-immunocompromised mice and CD4+ T cell content. In conclusion, we showed for the first time that lactoferrin, given orally to CP-immunosuppressed mice, could reconstitute a T-cell mediated immune response by renewal of the T cell pool.

Administration, Oral↗
PubMed2004

Study on the polymorphism of bovine lactoferrin gene and its relationship with mastitis.

Mastitis is a major cause of economic loss to the dairy industry. Lactoferrin (Lf) is known to contribute to resistance against bacterial infections. Hence, we decided to characterize the relevance between mastitis resistance and the variants of Lf gene. By using PCR-SSCP, five fragments within 5' region and all exons of bovine lactoferrin gene were amplified and identified the nucleotide diversity. For the five segments within the 5'-region: Lf5'-1, Lf5'-2, Lf5'-3, Lf5'-4, and Lf5'-5 from upstream to downstream, we found that three had base variation. Totally, mutations were observed in Lf5'-1, Lf5'-3, and Lf5'-5, exons 4, 8, 9, 11, 15, and intron 4. We analyzed the effects of all mutated loci on milk production traits with least squares method.

Animals↗