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PubMed1987

Isolation of lactoferrin cDNA from a human myeloid library and expression of mRNA during normal and leukemic myelopoiesis.

Lactoferrin is a major constituent of polymorphonuclear leukocyte granules and is present in mature neutrophils but not in blasts or promyelocytes. We have isolated a cDNA probe for lactoferrin and used it to study the synthesis of lactoferrin mRNA by normal and leukemic granulocyte precursors. The probe pHL-41 has been subcloned in phage m13 and characterized by restriction endonuclease analysis and nucleic acid sequencing. pHL-41 contains approximately 40% of the coding sequence of the lactoferrin gene. The 3' untranslated region includes a stop codon and a possible polyadenylation signal. There is a greater than 98% agreement between the cDNA-deduced amino acid sequence and that determined by analysis of the protein. Myeloid cells from normal bone marrow and circulating leukocytes from patients with chronic granulocytic leukemia contain lactoferrin mRNA transcripts that are indistinguishable in size and relative quantity. The human promyelocytic leukemia cell line HL-60 contains no lactoferrin mRNA. Induction of monocytic or granulocytic differentiation fails to induce the synthesis of detectable lactoferrin message. Similarly, studies with the human myeloblastic leukemia cell line PLB-985 reveal the inability of these cells to produce lactoferrin mRNA even under conditions that bring about morphologically demonstrable granulocytic differentiation. These data suggest that granulocytic differentiation in the leukemic cell lines is incomplete or defective. The presence of lactoferrin may play a role in the orderly expression of the genetic program leading to the development of the normal mature granulocyte.

Base Sequence↗

PubMed1985

Rapid radiometric assay used to assess lactoferrin in granulocytes.

We describe a rapid, precise, and sensitive radiometric assay for human lactoferrin. In this typical "sandwich"-type assay, anti-human lactoferrin is adsorbed onto a polystyrene sphere and bound lactoferrin is detected by the subsequent binding of 125I-labeled anti-human lactoferrin. The assay is accurate for lactoferrin concentrations of 5 to 1500 micrograms/L and takes about 2.5 h to complete. The within-assay and interassay variations (CV) are 5% and 13%, respectively. Neither lysozyme nor heparin, substances that form complexes with lactoferrin, interfered with lactoferrin measurement by this method. The assay has been applied to the measurement of lactoferrin in polymorphonuclear leukocytes of both healthy adults and neonates. We found significantly (p less than 0.001) less lactoferrin in the latter, an abnormality that may be related to known functional deficits of polymorphonuclear leukocytes during the newborn period.

Adult↗

PubMed2003

Heparin-interacting sites of bovine lactoferrin are involved in anti-adenovirus activity.

Lactoferrin, a member of the transferrin family of approximately 80 kDa, consists of a single polypeptide chain folded in two symmetric, globular lobes (N- and C-lobes), each able to bind one ferric ion. This glycoprotein, found in physiological fluids of mammals, plays an important role in immune regulation and in defense mechanisms against bacteria, fungi, parasites, and viruses. Although the antiviral activity of lactoferrin is one of the major biological functions of such protein, the mechanism of action is still under debate. We have investigated both the role of tryptic fragments of bovine lactoferrin and the mechanism of lactoferrin antiviral effect toward adenovirus infection in HEp-2 cells. The results obtained demonstrated that the anti-adenovirus activity of lactoferrin is mediated by the N-terminal half of the protein as the N-lobe was able to inhibit adenovirus infection, even if at lower extent than undigested lactoferrin, whereas C-lobe was ineffective. The results also showed that the anti-adenovirus action of lactoferrin and of its N-terminal peptide lactoferricin took place on virus attachment to cell membrane, mainly through competition for common glycosaminoglycan receptors. The data provide evidence that the anti-adenovirus activity of lactoferrin is mediated mainly by the cluster of positive charges at the N-terminus of whole molecule and that the N-terminal peptide lactoferricin alone is sufficient to prevent infection.

Adenoviruses, Human↗

PubMed1998

Bactericidal domain of lactoferrin: detection, quantitation, and characterization of lactoferricin in serum by SELDI affinity mass spectrometry.

Lactoferricin is a bioactive peptide fragment (3196 Da) derived from lactoferrin (80 kDa) that contains the bactericidal domain and the lymphocyte receptor-binding domain of lactoferrin. Although lactoferricin has been produced from lactoferrin by proteolytic digestion in vitro, its natural occurrence and distribution in vivo are still not clear, in part because of the absence of a suitable detection means. Surface-enhanced laser desorption/ionization (SELDI) was used to detect and characterize lactoferricin by affinity mass spectrometry. Human, porcine, and bovine lactoferricin in unfractionated serum samples were found to bind specifically to ligands presenting a terminal n-butyl group. SELDI was used to detect and quantify each species of lactoferricin in a manner that was independent of the presence of intact lactoferrin, partially degraded lactoferrin, and lactoferrin peptides containing the lactoferricin peptide sequence. The limit of detection of bovine lactofericin in serum was as low as 200 pg/ml. The FKCRRWQWR-homoserine/-homoserine lactone moiety of bovine lactoferricin, which includes the complete antimicrobial center (i.e., RRWQWR), was shown to be responsible for interaction with the n-butyl group. The SELDI procedure defined here is the only molecular recognition tool known to date that is capable of distinguishing the multi-functional lactoferricin domain located within structurally related but distinct forms of lactoferrin and its metabolic fragments. Enabling the direct quantitation of lactoferricin produced in vivo opens new opportunities to evaluate lactoferrin function.

Amino Acid Sequence↗

PubMed1994

Antimicrobial peptides of lactoferrin.

Lactoferrin was found to contain an antimicrobial sequence near its N-terminus which appears to function by a mechanism distinct from iron chelation. Antimicrobial peptides representing this domain were isolated following pepsin cleavage of human lactoferrin and bovine lactoferrin. The antimicrobial sequence was found to consist mainly of a loop of 18 amino acid residues formed by a disulfide bond between cysteine residues 20 and 37 of human lactoferrin, or 19 and 36 of bovine lactoferrin. The identified domain contains a high proportion of basic residues, like various other antimicrobial peptides known to target microbial membranes and it appears to be located on the surface of the folded protein allowing its interaction with surface components of microbial cells. The isolated domain, "lactoferrin", was shown to have potent broad spectrum antimicrobial properties and its effect was lethal causing a rapid loss of colony-forming capability. Such evidence points to the conclusion that this domain is the structural region responsible for the microbicidal properties of lactoferrin. The evidence also suggests the possibility that active peptides produced by enzymatic digestion of lactoferrin may contribute to the host defense against microbial disease.

Amino Acid Sequence↗

PubMed1998

Restricted spatiotemporal expression of lactoferrin during murine embryogenesis.

Lactoferrin is a member of the transferrin family of iron-binding proteins to which several physiological functions have been ascribed. While there is a wealth of evidence about the distribution and function of this protein in the adult, the expression and function, if any, of lactoferrin during embryogenesis has not been investigated. In the current study, the spatiotemporal distribution of lactoferrin was analyzed during normal murine embryonic development. This analysis demonstrated that lactoferrin is expressed in three distinct patterns during embryogenesis. First, lactoferrin is expressed at the 2-cell stage in the preimplantation embryo where it continues to be expressed until the blastocyst stage when expression ceases. The second phase of lactoferrin expression is not detected until the latter half of gestation when the protein is detected in the myeloid cells, beginning in the fetal liver at embryonic day 11 and later in the spleen and bone marrow coinciding with the onset and diversification of myelopoiesis in these organs during embryogenesis. Finally, lactoferrin is detected in a variety of glandular epithelial cells and/or their secretions, including respiratory and oral epithelia which is consistent with the expression pattern observed for this protein in the adult where it plays an important role in host defense at the mucosal surface. Taken together, these analyses indicate that the role of lactoferrin in the developing embryo is restricted to the preimplantation stage and development of first and second line host defense systems.

Animals↗

PubMed1998

Bacterial lactoferrin receptors.

Lactoferrin is thought to play a pivotal role in prevention of infection in the host and its ability to sequester iron from potential pathogens has been considered an important component of its antimicrobial function. A number of bacterial species in the Neisseriaceae have developed a mechanism for acquiring iron directly from this host glycoprotein which involves surface receptors capable of specifically binding lactoferrin. Initial attempts at identifying the receptor proteins in Neisseria and Moraxella species using affinity isolation with immobilized lactoferrin under high stringency conditions presumptively identified a single 100 kDa receptor protein, LbpA (formerly Lbp1). Under modified affinity isolation conditions a second 84 kDa lactoferrin binding protein was isolated and had been presumptively identified as LbpB. This protein was not isolated from a CopB-ve isogenic mutant of Moraxella catarrhalis, indicating that it was in fact CopB. However, another lactoferrin binding protein isolated under high stringency conditions, that comigrated with LbpA in most, but not all, M. catarrhalis strains, was identified by convalescent antisera. Its biochemical properties suggested that it indeed was LbpB. The identity of these proteins was confirmed by preparing isogenic mutants with the lbpA and lbpB genes. Growth studies with isogenic mutants deficient in LbpB, LbpA, CopB or FbpA were performed to evaluate their role in iron acquisition from lactoferrin. LbpA and FbpA were essential for this process, supporting prior models of the iron acquisition pathway. LbpB was not essential which is remniscent of studies with the bacterial transferrin receptors. The isogenic CopB-ve isogenic mutants were deficient in iron acquisition from both transferrin and lactoferrin, suggesting that it is a key component in both pathways. A model providing an alternate explanation of the data is presented. The role and surface accessibility of the lactoferrin receptor proteins suggests that they might be useful vaccine antigens and the preferentially reactivity of convalescent antisera with LbpB suggests that it may be the prime candidate.

Bacteria↗

PubMed2005

Lactoferrin: a modulator of immune and inflammatory responses.

Lactoferrin is an iron-binding glycoprotein of the transferrin family. Abundant expression and secretion of lactoferrin, in particular in milk and fluids of the digestive tract, are related to its implication in the first line of host defense. Lactoferrin is also a prominent component of the secondary granules of neutrophils (PMNs) and is released in infected tissues and blood during the inflammatory process. In addition to its direct antimicrobial properties, the abilities of lactoferrin to regulate the immune response and to protect against infection and septic shock have been described in numerous in vitro and in vivo studies. Although the cellular and molecular mechanisms that account for the modulation of the inflammatory and immune responses by lactoferrin are not yet totally elucidated, many are now established. At the cellular level, lactoferrin modulates the migration, maturation and function of immune cells. At the molecular level and in addition to iron binding, interactions of lactoferrin with a plethora of compounds, either soluble or membrane molecules, account for its modulatory properties. This paper reviews our current understanding of the cellular and molecular mechanisms that explain the regulatory properties of lactoferrin in host defence.

Animals↗

PubMed1999

Inhibition of poliovirus type 1 infection by iron-, manganese- and zinc-saturated lactoferrin.

In this study we investigated the inhibitory activity of different milk proteins on poliovirus infection in Vero cells. Proteins analyzed were mucin, alpha-lactalbumin, beta-lactoglobulin, and bovine and human lactoferrin. Viral cytopathic effect was not prevented by mucin, alpha-lactalbumin or beta-lactoglobulin, whereas the lactoferrins tested were able to inhibit the replication of poliovirus in a dose-dependent manner. Further experiments were carried out in which apo- and native lactoferrin or lactoferrin fully saturated with ferric, manganese or zinc ions were added to the cells during different phases of viral infection. Results obtained demonstrated that all lactoferrins were able to prevent viral replication when present during the entire cycle of poliovirus infection or during the viral adsorption step. Only zinc lactoferrin strongly inhibited viral infection when incubated with the cells after the viral attachment, being the inhibition directly correlated with the degree of zinc saturation. Our results demonstrated that all lactoferrins interfered with an early phase of poliovirus infection; zinc lactoferrin was the sole compound capable of inhibiting a phase of infection subsequent to virus internalization into the host cells.

Animals↗

PubMed1992

Identification of the bactericidal domain of lactoferrin.

We report the existence of a previously unknown antimicrobial domain near the N-terminus of lactoferrin in a region distinct from its iron-binding sites. A single active peptide representing this domain was isolated following gastric pepsin cleavage of human lactoferrin, and bovine lactoferrin, and sequenced by automated Edman degradation. The antimicrobial sequence was found to consist mainly of a loop of 18 amino acid residues formed by a disulfide bond between cysteine residues 20 and 37 of human lactoferrin, or 19 and 36 of bovine lactoferrin. Synthetic analogs of this region similarly exhibited potent antibacterial properties. The active peptide of bovine lactoferrin was more potent than that of human lactoferrin having effectiveness against various Gram-negative and Gram-positive bacteria at concentrations between 0.3 microM and 3.0 microM, depending on the target strain. The effect of the isolated domain was lethal causing a rapid loss of colony-forming capability. Our studies suggest this domain is the structural region responsible for the bacterial properties of lactoferrin.

Amino Acid Sequence↗

PubMed2005

Preventive effect of recombinant human lactoferrin in a rabbit preterm delivery model.

OBJECTIVE: Lactoferrin, an iron-binding glycoprotein found in cervical mucus and amniotic fluid, plays a defensive role against mucosal infections. This study examined the effect of recombinant human lactoferrin on preterm delivery in a rabbit model. STUDY DESIGN: Anesthetized rabbits were randomly assigned to receive either inoculation with Escherichia coli or saline solution and to receive treatment with or without recombinant human lactoferrin inserted into the cervix 2 hours before bacterial inoculation (condition A: saline + saline; condition B: E coli + saline; condition C: E coli + recombinant human lactoferrin). E coli , saline solution, and recombinant human lactoferrin were inserted into the cervix using a hysteroscope and a sterile polyethylene cannula. Fetus survival rate and days to delivery after inoculation were monitored and tumor necrosis factor-alpha concentrations were measured in maternal serum and amniotic fluid. RESULTS: Fetus survival for conditions A, B, and C were 95.7%, 0%, and 32.6%, respectively, whereas pregnancy continuation was 7.00 +/- 0 days, 3.25 +/- 0.43 days, and 4.85 +/- 1.77 days, respectively. CONCLUSION: Cervical recombinant human lactoferrin administration increased fetal survival and extended pregnancy. Lactoferrin has an anti-inflammatory action as well as an antibacterial action, suggesting that recombinant human lactoferrin has the potential to prevent preterm delivery originating from cervical infection in the clinical setting.

Animals↗

PubMed2004

Inhibition of cytomegalovirus infection by lactoferrin in vitro and in vivo.

Lactoferrin is an antimicrobial agent, that, amongst other viruses, inhibits cytomegalovirus (CMV). In this study, we addressed the mechanism(s) by which lactoferrin interacts with CMV and its target cells to inhibit infection. We also studied the antiviral activity of lactoferrin in vivo in rat CMV models with and without immune suppression. We cationized a protein of similar molecular weight, i.e. human serum albumin (HSA), as well as a protein with a smaller molecular weight (beta-lactoglobulin). While HSA itself displayed no anti-CMV activity in vitro, cationic HSA inhibited CMV replication to a similar extent as lactoferrin. Time-of-addition assays indicated that all cationic proteins interacted with an early event in the infection and pre-incubation of cells rather than of virus significantly reduced CMV replication. Rats were treated with lactoferrin (4, 40 or 160 mg/kg, intravenously), beginning at 6h after CMV administration. Subsequently, the rats were treated three times a week. As a positive control, CMV-infected rats were treated with cidofovir, and this agent proved to be highly active in the rat models for CMV. Treatment with lactoferrin was beneficial when infection was initiated with cell-free virus, but not with virus-infected leukocytes. Lactoferrin treatment led to a 10-fold reduction in the final virus titers (salivary glands) at 4 weeks after infection in the immunocompromised rats. Lactoferrin exerted its effects via inhibition of cell entry rather than via stimulation of the immune system.

Animals↗

PubMed2006

A novel apoptosis cascade mediated by lysosomal lactoferrin and its participation in hepatocyte apoptosis induced by D-galactosamine.

A new apoptosis cascade mediated by lysosomal lactoferrin was found in apoptotic liver induced by d-galactosamine. Caspase-3 and lactoferrin were increased in the apoptotic liver cytoplasm and serum transaminases were elevated. Recombinant lactoferrin stimulated procaspase-3 processing at 10(-6)-10(-7)M to an extent similar to that by granzyme B in vitro. Lactoferrin changed procaspase-3 structure susceptible to the processing. Synthetic peptide Y(679)-K(695) in lactoferrin molecule inhibited the processing of procaspase-3 by lactoferrin. Lactoferrin in lysosomes was decreased and lactoferrin released into cytoplasm was increased quantitatively in d-galactosamine induced apoptotic liver, and procaspase-3 in cytoplasm was processed to caspase-3.

Animals↗

PubMed1977

Radioimmunoassay for murine lactoferrin, a protein marker of myeloid and mammary epithelial secretory cell differentiation.

A radioimmunoassay was developed for murine lactoferrin (LF), a non-heme, iron-binding glycoprotein which appears to be a specific biochemical marker of differentiation in several cell types. Lactoferrin was labeled with 125I by the chloramine-T method to yield a product having 20 muCi/mug protein and an isotope incorporation of 0.6 atoms of 125I per molecule. Separation of bound and free lactoferrin was accomplished by either of two procedures, a double-antibody technique or precipitation in the presence of 50% saturated ammonium sulfate. The entire assay, including counting, was accomplished in less than 2 days and had a lower limit of sensitivity and a range of 1 ng/ml and 1-32 ng/ml, respectively, using rabbit antiserum in a dilution of about 1:10,000. The binding between LF and rabbit antiserum exhibited two association constants having values of 1.8 x 10(11) and 1 x 10(9) l/mole. The assay was specific for lactoferrin and no cross-reactivity was observed with transferrin, a similar non-heme, iron-binding glycoprotein. Human lactoferrin specifically reacted with anti-mouse lactoferrin, but the binding was approximately 8000 times weaker than observed with mouse lactoferrin. Values for lactoferrin in milk and bone marrow granulocytes were obtained which agreed with levels obtained using other methods.

Animals↗

PubMed1981

Basal and reflex human tear analysis. II. Chemical analysis: lactoferrin and lysozyme.

Unstimulated basal tears and stimulated tears were collected from normal controls, keratoconjunctivitis sicca (KCS) patients, and contact lens (CL) wearers. Basal tear volume (Periopaper) and reflex tear volume (Schirmer Strip) were measured and tears eluted from their respective strip with a TMED-acetic acid buffer. Lactoferrin and lysozyme concentrations were measured in the eluates. Concentration of lysozyme in basal tears was: 65 +/- 43 mg% in normals; 44 +/- 26 mg% in KCS, and 81 +/- 50 mg% in CL wearers. Concentration of lysozyme in reflex tears was: 160 +/- 73 mg% in normals, 74 +/- 41 mg% in KCS, and 186 +/- 83 mg% in CL wearers. Concentration of lactoferrin in basal tears was 137 +/- 102 mg% in normals, 154 +/- 82 mg% in KCS, and 157 +/- 80 mg% in CL wearers. Concentrations of lactoferrin in reflex tears was: 327 +/- 187 mg% in normals; 171 +/- 69 mg% in KCS, and 302 +/- 160 mg% in CL wearers. The lactoferrin concentration in all tear samples was consistently higher (1.6-3.5 times) than lysozyme. In basal tears, lactoferrin concentrations were not significantly different in the three groups. In reflex tears, however, lactoferrin was significantly lower in KCS than normal or CL wearers. The concentration of lysozyme in both basal and reflex tears was significantly lower in the KCS when compared to normal or CL wearers. Lysozyme and lactoferrin concentrations in both basal and reflex tears were similar in CL wearers and normal controls. The sampling and elution of basal and reflex tears as described appears to be a feasible technique for analysis of lysozyme and lactoferrin concentrations by the electroimmunodiffusion technique and has potential diagnostic value.

Contact Lenses↗

PubMed2000

Lactoferrin in infant formulas: effect on oxidation.

Lactoferrin is an iron transport protein present in human milk at an average concentration of 1.4 mg/mL. Commercially modified infant formulas based on cow's milk contain much lower amounts of lactoferrin (0.1 mg/mL lactoferrin) and soy based formulas have none. In addition to its role in iron transport, lactoferrin has bacteriostatic and bactericidal activities. Infant formulas are supplemented with relatively large amounts of iron (up to 12 mg/L). The effect of various concentrations of added lactoferrin and supplemental iron on lipid oxidation was tested in two different infant formulas. The extent of oxidation in the formulas as a function of time was determined by formation of hydroperoxides, production of hexanal, and fluorescence. On the basis of all three of these determinations, lactoferrin acted as an antioxidant in the absence and presence of different concentrations of supplemented iron. Lactoferrin inhibited oxidation in a concentration-dependent manner even at concentrations beyond its capacity to bind iron at its two high affinity binding sites. Lactoferrin can be used, therefore, as a dual purpose additive in infant formulas and similar food products for its antioxidant and its antimicrobial properties.

Humans↗

PubMed1999

Effect of lactoferrin on oxidative stability of corn oil emulsions and liposomes.

Interest in using lactoferrin in foods for its antimicrobial activity inspired the present study of its antioxidant activity. Natural bovine lactoferrin inhibited oxidation in buffered corn oil emulsions and lecithin liposome systems at pH 6.6 and 50 degrees C. The antioxidant activity increased with lactoferrin concentration in both phosphate- and Tris-buffered emulsions, but not in both buffered liposome systems. A mixture of 1 microM lactoferrin and 0.5 microM ferrous ions was a significantly better antioxidant than 1 microM lactoferrin alone in Tris-buffered emulsions and in phosphate-buffered liposomes. Lactoferrin was a prooxidant at 1 microM in phosphate-buffered liposomes and at 15 and 20 microM in Tris-buffered liposomes. Copper was a stronger prooxidant than iron in both buffered emulsions. Lactoferrin decreased the prooxidant effect of iron, but not of copper, in emulsions. The antioxidant or prooxidant activities of lactoferrin depended on the lipid system, buffer, its concentration, the presence of metal ions, and oxidation time.

Animals↗

PubMed2004

Lactoferrin and host defence: an overview of its immuno-modulating and anti-inflammatory properties.

Lactoferrin is a member of the transferrin family of iron-binding glycoproteins that is abundantly expressed and secreted from glandular epithelial cells. In secretions, such as milk and fluids of the intestinal tract, lactoferrin is an important component of the first line of host defence. During the inflammatory process, lactoferrin, a prominent component of the secondary granules of neutrophils (PMNs), is released in infected tissues and in blood and then it is rapidly cleared by the liver. In addition to the antimicrobial properties of lactoferrin, a set of studies has focused on its ability to modulate the inflammatory process and the overall immune response. Though many in vitro and in vivo studies report clear regulation of the immune response and protective effect against infection and septic shock by lactoferrin, elucidation of all the cellular and molecular mechanisms of action is far from being achieved. At the cellular level, lactoferrin modulates the migration, maturation and function of immune cells. At the molecular level and in addition to iron binding, interactions of lactoferrin with a plethora of compounds, either soluble or membrane molecules, account for its modulatory properties. This paper reviews our current understanding of the cellular and molecular mechanisms that explain the regulatory properties of lactoferrin in host defence.

Animals↗