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PubMed2006

Effect of lactoferrin on enteroaggregative E. coli (EAEC).

We previously demonstrated that lactoferrin inhibits adherence of enteropathogenic Escherichia coli to HEp-2 cells and decreases invasiveness of Shigella flexneri in HeLa cells by disruption of the type III secretory system (TTSS) of both enteropathogens. To determine whether these effects were specific to the TTSS, we assessed the activity of bovine lactoferrin on enteroaggregative E. coli (EAEC), enteropathogens whose virulence is not TTSS dependent. Bovine lactoferrin at a concentration of 1.0 and 0.1 mg/mL inhibited EAEC growth. Saturation with iron reversed the bacteriostatic effect. Lactoferrin under nonbacteriostatic conditions decreased EAEC adherence to HEp-2 cells as evaluated by microscopy and CFUs; this effect was not iron dependent. Lactoferrin inhibited EAEC biofilm formation and increased autoagglutination. Lactoferrin blocks EAEC adherence by inducing release and degradation of aggregative adherence fimbria, a key element of EAEC pathogenesis. We hypothesized that lactoferrin binding to lipid A of lipopolysaccharide disrupts the virulence proteins anchored to the bacterial outermembrane. These data suggest that the effect of lactoferrin on surface proteins is not restricted to organisms having a TTSS.

Adhesins, Escherichia coli↗

PubMed2002

Lactoferrin reduces colitis in rats via modulation of the immune system and correction of cytokine imbalance.

Natural immunomodulator lactoferrin is known to exert an anti-inflammatory effect. However, there have been no studies that examine the mode of action of lactoferrin in reducing intestinal damage. We investigated the effect of lactoferrin on a trinitrobenzenesulfonic acid (TNBS)-induced colitis model in rats. Bovine lactoferrin was given once daily through gavage, starting 3 days before (preventive mode) or just after TNBS administration (treatment mode) until death. The distal colon was removed to be examined. Colitis was attenuated by lactoferrin via both modes in a dose-dependent manner, as reflected by improvement in macroscopic and histological scores and myeloperoxidase activity. Lactoferrin caused significant induction of the anti-inflammatory cytokines interleukin (IL)-4 and IL-10, significant reductions in the proinflammatory cytokines tumor necrosis factor-alpha and IL-1beta, and downregulation of the nuclear factor-kappaB pathway. We concluded that lactoferrin exerts a protective effect against colitis in rats via modulation of the immune system and correction of cytokine imbalance. Lactoferrin has potential as a new therapeutic agent for inflammatory bowel disease.

Animals↗

PubMed1990

Iron uptake from transferrin and lactoferrin by rat intestinal brush-border membrane vesicles.

Interaction of 59Fe-labeled rat transferrin, human lactoferrin, and bovine lactoferrin with rat small intestinal brush-border membrane vesicles was investigated with the use of a rapid filtration technique. Specific binding of 59Fe-labeled rat transferrin and bovine lactoferrin to brush-border membrane vesicles from suckling and adult rats was identified. In contrast, no binding of human lactoferrin occurred. The presence of transferrin receptors on the brush-border membrane of suckling rats was confirmed by immunoblotting, and the molecular mass of the receptor was 96 kDa under nonreducing conditions. Scatchard plot analysis indicated 2.4 x 10(14) binding sites/mg of membrane protein with an affinity constant (Ka) of 4.9 x 10(6) M-1 for rat milk transferrin and 2.2 x 10(14) binding sites/mg of membrane protein with a Ka of 3.2 x 10(6) M-1 for bovine lactoferrin. Bovine lactoferrin competitively inhibited the binding of rat transferrin to the brush-border membrane vesicles. Deglycosylation of rat transferrin and bovine lactoferrin had no influence on the binding of these proteins. The results suggested that bovine lactoferrin bound to the receptor for rat transferrin on the brush-border membrane and that the polypeptide chain rather than the glycan moiety is responsible for the interaction of these proteins with the rat brush-border membrane.

Aging↗

PubMed1981

Lactoferrin enhances hydroxyl radical production by human neutrophils, neutrophil particulate fractions, and an enzymatic generating system.

During phagocytosis, neutrophils take oxygen from the surrounding medium and convert it to superoxide anion (O2-) and hydrogen peroxide (H2O2). Hydroxyl radical (.OH), a particularly potent oxidant, is believed to be produced by interaction between O2- and H2O2 in the presence of iron, according to the Haber-Weiss reactions. Production of .OH by whole human neutrophils, by particulate fractions from human neutrophils disrupted after stimulation, and by a xanthine oxidase system was measured by conversion of alpha-keto-gamma-methiol butyric acid to ethylene. FeCl3 or ferric EDTA enhanced ethylene production in all three systems by 155--406% of base line at a concentration of 50--100 microM. Iron-saturated human milk lactoferrin, 100 nM, increased ethylene generation by 127--296%; and purified human neutrophil lactoferrin, 10 nM, enhanced ethylene production by 167--369%. Thus, iron bound to lactoferrin was approximately 5,000 times more effective in producing an enhancement in ethylene generation than iron derived from FeCl3 or ferric EDTA. O2- and H2O2 were required for ethylene production in the presence of lactoferrin, since superoxide dismutase inhibited ethylene formation in the three systems by 76--97% and catalase inhibited by 76--98%. Ethylene production in the presence of lactoferrin was inhibited by the .OH scavengers mannitol, benzoate, and thiourea by 43--85, 45--94, and 76--96%, respectively. Thus, most of the ethylene production could be attributed to oxidation of alpha-keto-gamma-methiol butyric acid by .OH. The ability of neutrophil lactoferrin to provide iron efficiently to the oxygen radical-generating systems is compatible with a role for lactoferrin as regulator of .OH production. As such, lactoferrin may be an important component in the microbicidal activity of neutrophils.

Benzoates↗

PubMed1989

Selective defect in myeloid cell lactoferrin gene expression in neutrophil specific granule deficiency.

Neutrophil specific granule deficiency (SGD) is a congenital disorder associated with an impaired inflammatory response and a deficiency of several granule proteins. The underlying abnormality causing the deficiencies is unknown. We examined mRNA transcription and protein synthesis of two neutrophil granule proteins, lactoferrin and myeloperoxidase in SGD. Metabolically labeled SGD nucleated marrow cells produced normal amounts of myeloperoxidase, but there was no detectable synthesis of lactoferrin. Transcripts of the expected size for lactoferrin were detectable in the nucleated marrow cells of two SGD patients, but were markedly diminished in abundance when compared with normal nucleated marrow cell RNA. Because lactoferrin is secreted by the glandular epithelia of several tissues, we also assessed lactoferrin in the nasal secretions of one SGD patient by ELISA and immunoblotting. Nasal secretory lactoferrin was the same molecular weight as neutrophil lactoferrin and was secreted in normal amounts. From these data, we conclude that lactoferrin deficiency in SGD neutrophils is tissue specific and is secondary to an abnormality of RNA production. We speculate that the deficiency of several granule proteins is due to a common defect in regulation of transcription that is responsible for the abnormal myeloid differentiation seen in SGD patients.

Blotting, Northern↗

PubMed1991

Killing of gram-negative bacteria by lactoferrin and lysozyme.

Although lactoferrin has antimicrobial activity, its mechanism of action is not full defined. Recently we have shown that the protein alters the Gram-negative outer membrane. As this membrane protects Gram-negative cells from lysozyme, we have studied whether lactoferrin's membrane effect could enhance the antibacterial activity of lysozyme. We have found that while each protein alone is bacteriostatic, together they can be bactericidal for strains of V. cholerae, S. typhimurium, and E. coli. The bactericidal effect is dose dependent, blocked by iron saturation of lactoferrin, and inhibited by high calcium levels, although lactoferrin does not chelate calcium. Using differing media, the effect of lactoferrin and lysozyme can be partially or completely inhibited; the degree of inhibition correlating with media osmolarity. Transmission electron microscopy shows that E. coli cells exposed to lactoferrin and lysozyme at 40 mOsm become enlarged and hypodense, suggesting killing through osmotic damage. Dialysis chamber studies indicate that bacterial killing requires direct contact with lactoferrin, and work with purified LPS suggests that this relates to direct LPS-binding by the protein. As lactoferrin and lysozyme are present together in high levels in mucosal secretions and neutrophil granules, it is probable that their interaction contributes to host defense.

Calcium↗

PubMed1983

Nuclear localization of lactoferrin in the human granulocyte: Artifact incurred during slide preparation.

Within the blood cells, lactoferrin is found only in the late stage neutrophilic granulocytes. Lactoferrin first appears in these cells during the myelocyte stage of development coincidentally with the specific or secondary granules. Most investigators report a cytoplasmic immunocytochemical localization reaction within the granulocyte. However, others have observed a prominent nuclear localization reaction. Treating the cells with certain fixatives was shown to prevent the relocation of lactoferrin from the cytoplasm to the nucleus when the localization was done on granulocytes prepared by smearing. The present study demonstrated that the relocation of lactoferrin is only a problem when cells were smeared or cytocentrifuged onto slides or fractionated for the purpose of isolating cellular organelles. Under these conditions the selection of fixative is an important consideration. Exposing isolated lactoferrin to a fixative effective in retaining lactoferrin in the cytoplasm of granulocytes smeared on slides did not alter a number of its physical properties. The results suggest that maintenance of the normal cytoarchitecture or effect of fixative on other cellular components prevents the relocation of lactoferrin within the cell during tissue processing and the direct action of fixation on lactoferrin is probably not responsible for this effect.

Acetone↗

PubMed1990

Iron is not required in the lactoferrin stimulation of thymidine incorporation into the DNA of rat crypt enterocytes.

Lactoferrin has been identified as a factor in human colostrum that accounts for increased incorporation of thymidine into the DNA in an in vitro rat crypt enterocyte bioassay. We have examined lactoferrin-stimulated thymidine incorporation by comparing the effects of iron-free lactoferrin (apolactoferrin) with those of iron-saturated lactoferrin (diferric lactoferrin) under conditions that inhibit the transfer of iron between these iron-binding proteins in the bioassay system. In addition, we have compared the dose-response relationships of diferric lactoferrin and apolactoferrin. The results demonstrated that lactoferrin, independent of iron-binding states, promoted the incorporation of thymidine into the DNA of rat crypt enterocytes. These observations suggest a previously unreported nutritional role for lactoferrin that is independent of its iron-binding capacity.

Animals↗

PubMed1999

Lactoferrin: a multifunctional glycoprotein involved in the modulation of the inflammatory process.

Lactoferrin is an iron-binding glycoprotein found in exocrine secretions of mammals and released from neutrophilic granules during inflammation. This review describes the biological roles of lactoferrin in host defence. Secreted lactoferrin exerts antimicrobial action either by chelation of iron or by destabilization of bacterial membranes. Furthermore, lactoferrin modulates the inflammatory process, mainly by preventing the release of cytokines from monocytes and by regulating the proliferation and differentiation of immune cells. Some of these activities are related to the ability of lactoferrin to bind lipopolysaccharides (LPS) with high affinity. Indeed, recent in vitro studies indicate that lactoferrin is able to compete with the LPS-binding protein for LPS binding and therefore to prevent the transfer of LPS to CD14 present at the surface of monocytes. Moreover, the prophylactic properties of lactoferrin against septicemia in vivo have been demonstrated. Taken as a whole, these observations strongly suggest that lactoferrin is one of the key molecules which modulate the inflammatory response.

Animals↗

PubMed2006

Coadsorption of human milk lactoferrin into the dipalmitoylglycerolphosphatidylcholine phospholipid monolayer spread at the air/water interface.

The coadsorption of human milk lactoferrin into a spread monolayer of dipalmitoylglycerol phosphatidylcholine (DPPC) at the air/water interface has been studied by neutron reflection. The system is a good model of the preocular tear film outer interface, which was the motivation for the study. The association of the protein with the surface was indicated by an increase of the surface pressure exerted by the DPPC monolayer. The extent of lactoferrin coadsorption was found to decrease with increasing surface pressure in the lipid monolayer, a trend consistent with the observation reported for other proteins, such as lysozyme and beta-lactoglobulin. The neutron reflectivity measurements were subsequently carried out at the three surface pressures of 8, 15, and 35 mN/m to examine the structure and composition of lactoferrin coadsorbed at the interface. Whereas the DPPC monolayer effectively prevented lactoferrin insertion at the high surface pressure, a measurable amount of lactoferrin was found at the air/water interface at the two lower surface pressures. At 15 mN/m it was difficult to identify the distribution of lactoferrin with respect to the DPPC monolayer, due to its relatively low adsorbed amount and much broader distribution. At the lowest surface pressure of 8 mN/m, the lactoferrin coadsorption was found to increase with time over the first few hours. After 5 h the distribution of the lactoferrin layer became similar to, though quantitatively lower than, that adsorbed in the absence of the DPPC monolayer. It is characterized by a top dense sublayer of 15 A with a bottom diffuse sublayer of 60 A, indicating structural unfolding induced by surface adsorption under these conditions.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2005

Full length and delta lactoferrin display differential cell localization dynamics, but do not act as tumor markers or significantly affect the expression of other genes.

Lactoferrin is a secreted protein related to transferrin. Lactoferrin indirectly protects host cells against foreign insults by killing bacteria, scavenging free iron, and binding to receptors required for viral invasion. However, lactoferrin is also proposed to act directly on cells as a transcription factor and tumor suppressor gene. In addition to full length lactoferrin, a truncated form, called delta lactoferrin, can also be produced by alternative splicing. We show here that transformed and nontransformed cells are equally able to express both full length and delta lactoferrin. Moreover, both forms of lactoferrin failed to substantially modulate the expression of other genes. Thus, lactoferrin does not seem to directly control gene expression or inhibit tumor cell growth.

Alternative Splicing↗

PubMed2000

Effects of pasteurization of colostrum on subsequent serum lactoferrin concentration and neutrophil superoxide production in calves.

OBJECTIVE: To determine the effects of pasteurization of colostrum on serum lactoferrin concentration and neutrophil oxidative function by comparing values from calves given pasteurized (76 C, 15 minutes) colostrum versus calves given fresh frozen colostrum. ANIMALS: 8 Holstein bull calves were used to study the effects of pasteurization of colostrum on the absorption of lactoferrin and neutrophil oxidative burst. Three additional calves were used to study the effect of exogenous lactoferrin on neutrophil oxidative burst. METHODS: Calves were fed fresh frozen or heat pasteurized colostrum (76 C for 15 minutes) via esophageal feeder within 4 hours of birth. Neutrophils were isolated from whole blood samples. Neutrophil oxidative burst was induced by phorbol ester (300 ng/ml) stimulation of cells (1 X 10(6) cells) at 37 C. Serum lactoferrin concentrations were compared, using immunoblot analysis. Serum IgG concentrations were determined by radial immunoassay. Comparisons were made between the use of the 2 types of colostrum in calves by measuring subsequent serum IgG and lactoferrin concentrations and neutrophil superoxide production. RESULTS: Serum IgG and lactoferrin concentrations increased more in calves receiving fresh frozen colostrum. Neutrophil superoxide production was higher in neutrophils prepared from calves receiving fresh frozen colostrum. Colostral lactoferrin addition to neutrophil incubations resulted in increased oxidative burst. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with calves given fresh frozen colostrum, calves given pasteurized colostrum had decreased serum IgG and lactoferrin concentrations and neutrophil superoxide production 24 hours after administration. These results suggest that pasteurizing bovine colostrum at 76 C for 15 minutes has substantial effects on passive transfer of proteins and neutrophil function.

Animal Feed↗

PubMed1993

An enzyme-linked immunosorbent assay for plasma-lactoferrin. Concentrations in 362 healthy, adult blood donors.

Very different concentrations of plasma-lactoferrin in healthy adults have been reported in the literature. We compared three commercially available lactoferrins and lactoferrin purified in our laboratory as calibrators in an ELISA. No statistical differences among these preparations of lactoferrin were detected. The concentration of purified lactoferrin was measured by dry weight, and efforts were made in order to minimize loss of purified lactoferrin by adhesion to tubes etc. and thus, secure accuracy of the method. Dilutions were made in PBS 0.01 mol l-1 with NaCl 0.436 mol l-1, (NH4)2SO4 0.5 mol l-1, BSA 5 gl-1 and normal rabbit IgG 10 mg l-1, which was shown to give parallel dilution curves of primary calibrator, secondary calibrator and plasma samples. No significant difference in the content of lactoferrin in neutrophils (median; range) among men (1.78; 0.83-4.48 micrograms 10(-6) neutrophils; n = 20) and women (2.12; 1.16-9.30 micrograms 10(-6) neutrophils; n = 14) was found. Lactoferrin was analysed in EDTA-plasma obtained from 135 female and 227 male blood donors. Median concentrations were 84.7 and 97.8 micrograms l-1 respectively, while 2.5% and 97.5% reference limits (with 90% confidence intervals) were estimated to 42.9 (38.7-47.4) micrograms l-1 and 166.9 (151.0-186.3) micrograms l-1 for women and 52.3 (49.1-55.6) micrograms l-1 and 189.9 (175.9-206.4) micrograms l-1 for men, respectively.

Adult↗

PubMed1991

Potent bactericidal activity of bovine lactoferrin hydrolysate produced by heat treatment at acidic pH.

A hydrolysate of bovine lactoferrin produced by heat treatment under acidic conditions had antibacterial activity at concentrations of 10 micrograms/ml in the culture medium. The optimal degree of hydrolysis for this activity was about 10%. Heat-treated lactoferrin, treated at pH 2.0 and 120 degrees C for 15 min and degree of hydrolysis of about 10%, had no Fe-binding capacity (0%) and less antigenicity (about 10(-6) than untreated lactoferrin. Heat-treated lactoferrin increased in antibacterial activity, and the activity was maintained in an Fe-rich medium. After fractionation of heat-treated lactoferrin by reverse-phase HPLC, several peptide fractions were found that had strong antibacterial activity. It was suggested that lactoferrin latently contains at least one bactericidal domain that is activated upon release by limited acid hydrolysis of the protein. The bactericidal activity of the peptide fragments of lactoferrin was shown to have no relation to Fe chelation, in contrast with the antibacterial mechanism of native lactoferrin.

Animals↗

PubMed1996

Elevation of lactoferrin gene expression in developing, ductal, resting, and regressing parenchymal epithelium of the ruminant mammary gland.

Accumulation of lactoferrin mRNA in mammary tissue from virgin, pregnant, lactating, and involuting ewes and cows was localized using 35S-labeled cRNA probes. Expression of lactoferrin was low in the glands of virgin animals. In the glands of animals in early pregnancy, very high expression occurred in the ducts and immature alveoli, but expression tended to decrease as the alveoli matured. In the lactating and involuting gland, expression was generally low or absent in actively secreting alveoli and high in alveoli that had an accumulation of vesicles in the lumen and secretory epithelium, which was indicative of stasis. Occasionally, expression of lactoferrin was seen in cells that appeared to be secretory, particularly in involuting glands. Lactoferrin mRNA was expressed not only at different sites from other milk protein genes, such as alpha-lactalbumin and alpha s1-casein, but also during different stages of mammary development, supporting the view that the expression of lactoferrin is regulated differently from that of other milk proteins. For all ewes and cows, lactoferrin mRNA was detected in the epithelial ducts of the mammary parenchyma and the teat in a gradient that increased in ducts nearer the teats. The expression of lactoferrin in the ductal epithelium close to the teat was consistent with the antibacterial role of lactoferrin.

Animals↗

PubMed1999

Enhancement of the activity of novobiocin against Escherichia coli by lactoferrin.

The activity of novobiocin against Escherichia coli ATCC 25922 and three E. coli strains that were isolated from cases of bovine mastitis was determined in timekill studies in the presence of bovine lactoferrin. Lactoferrin alone did not affect the growth of any of the strains of E. coli. A combination of 1.0 mg/ml of lactoferrin and novobiocin at 1/16x minimum inhibitory concentration (MIC) was bactericidal for E. coli ATCC 25922. When the concentration was increased to 3.0 mg/ml of lactoferrin, novobiocin was bactericidal at 1/64x MIC. Among the mastitis strains tested, 6789 and 6806 were more susceptible to killing by novobiocin than was strain 6800. Strains 6789 and 6806 were killed when treated with novobiocin concentrations of 2, 1/2, and 1/4x MIC. When these strains were also treated with lactoferrin at 3.0 mg/ml, there was a bacteriostatic effect at novobiocin concentrations of 1/8 and 1/16x MIC for strains 6789 and 6800. Strain 6806 appeared to be more susceptible to the combination of lactoferrin and novobiocin as was evidenced by a bactericidal effect over the 24-h testing period. The combination treatment with cephapirin and lactoferrin showed that there was a synergistic bactericidal effect against all of the E. coli strains tested. These studies indicate that lactoferrin can potentiate the activity of antibiotics against Gram-negative bacteria.

Animals↗

PubMed2003

Expression of lactoferrin on neutrophil granulocytes from synovial fluid and peripheral blood of patients with rheumatoid arthritis.

OBJECTIVE: To analyze lactoferrin expression on synovial fluid (SF) and peripheral blood neutrophils of patients with rheumatoid arthritis (RA) and to compare it with the lactoferrin expression on neutrophils from patients with osteoarthritis (OA). METHODS: Paired samples of peripheral blood and SF were obtained from 14 patients with RA and 9 patients with OA. Lactoferrin expression was evaluated on cell surfaces by cytofluorimetric analysis utilizing both polyclonal antibodies and the monoclonal anti-lactoferrin antibody AGM 2.29. Data are presented as mean fluorescence intensity. RESULTS: In patients with RA, the expression of membrane lactoferrin was significantly increased on SF neutrophils in comparison with those in peripheral blood. This increase was found using both polyclonal antibodies and AGM 2.29 (p = 0.0001, p = 0.0017, respectively). In patients with OA, the difference was not significant. In addition, lactoferrin expression on SF neutrophils of patients with RA was significantly increased compared with that found on SF neutrophils of patients with OA (polyclonal antibodies, p = 0.0015; AGM 2.29, p = 0.005). In patients with RA, no correlation was found between lactoferrin expression and disease activity. CONCLUSION: Our results provide evidence for an activation of neutrophil granulocytes at site of inflammation in RA and indicate that lactoferrin surface expression represents a reliable neutrophil activation marker.

Adult↗

PubMed1992

Lactoferrin specifically inhibits endocytosis of chylomicron remnants but not alpha-macroglobulin.

Our recently found nonlipoprotein inhibitor of chylomicron remnant uptake, lactoferrin, has been investigated in vivo and in vitro. Lipoprotein lipase extracted triglycerides from chylomicrons, doubly labeled with [3H]retinol/[14C]oleate, in the presence of lactoferrin normally. The subsequent uptake of remnants into liver was retarded considerably. In the intact rat, chylomicron remnants (CRs), predominantly labeled in the apoB48 moiety by 125I, were excluded from the hepatic endosomal compartment in the presence of lactoferrin as shown in subcellular fractionation studies of rat livers. In tissue culture, internalization of [125I]chylomicron remnants was inhibited in the presence of 14 pM lactoferrin by 70%. Upon removal of lactoferrin, internalization was rapidly restored. Protease digestion eliminated the inhibitory effect completely. Modification of arginine residues with cyclohexanedione reversibly removed the inhibitory potency of lactoferrin. We located by molecular modeling an alpha-helical segment in lactoferrin on the exposed surface of the molecule containing the sequence Arg-X-X-Arg-Lys-X-Arg, which resembles the receptor recognition structure in apolipoprotein E (apoE). This firmly established ligand correspondence with apoE, the candidate ligand for CR recognition by the receptor. Finally, the postulated second function of low density lipoprotein receptor-related protein, uptake of alpha-2-macroglobulin (alpha 2M) was found to be distinct from lipoprotein binding, since lactoferrin inhibited CR but not alpha 2M internalization. In addition, CR uptake was not affected by alpha 2M. We conclude that if a bifunctional receptor were to operate, its diverse functions were exerted by independently operating substructures. The results of our in vivo and cell culture experiments are, however, entirely compatible with the existence of two receptors as well.

Adenosine Triphosphatases↗