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PubMed2001

Antifungal effects of lysozyme and lactoferrin against genetically similar, sequential Candida albicans isolates from a human immunodeficiency virus-infected southern Chinese cohort.

A variety of innate defense factors in saliva such as lysozyme and lactoferrin contribute to mucosal protection and modulate Candida populations in the oral cavity. It is also known that in human immunodeficiency virus (HIV)-infected individuals significant variations in the concentrations of lysozyme and lactoferrin in saliva occur during disease progression. Therefore, the aim of this study was to determine the in vitro susceptibility to human lactoferrin and hen egg white lysozyme of genotypically similar oral Candida albicans isolates obtained from six HIV-infected ethnic Chinese during sequential visits over a 12-month period. The similarity of the genotypes (50 in total) was evaluated using a randomly amplified polymorphic DNA assay. A blastospore viability assay was performed to evaluate the sensitivity of the organisms to lysozyme and lactoferrin. Exposure to physiological concentrations of either lysozyme (30 microg/ml) or lactoferrin (20 microg/ml) caused a rapid loss of viability among all isolates to a varying extent. None of the sequential C. albicans isolates demonstrated significant differences in sensitivity to either protein from one visit to the next; similar results were noted when the different genotypes from the same individual were compared. On Spearman correlation analysis of two genotypes that were sequentially isolated from a single patient, a significant negative correlation between lysozyme (r = -0.88; P < 0.02) (but not lactoferrin) resistance and the duration of HIV disease was seen. These results imply that a minority of C. albicans isolates that persist intraorally in individuals with HIV disease develop progressive resistance to innate salivary antifungal defenses such as lysozyme, possibly as an adaptive response. However, the vast majority of the Candida isolates appear to succumb to these nonspecific host immune mediators abundantly present in the oral environment.

AIDS-Related Opportunistic Infections↗

PubMed2005

Lactoferrin Glu561Asp facilitates secondary amyloidosis in the cornea.

AIM: To elucidate the pathogenic mechanism of amyloid formation in corneal amyloidosis with trichiasis. METHODS: Ophthalmological examination was performed in nine patients to determine secondary corneal amyloidosis with trichiasis. Congo red staining and immunohistochemistry using anti-human lactoferrin antibody were used for biopsied corneal samples. For genetic analyses, single strand conformation polymorphism (SSCP), direct DNA sequence analysis, and polymerase chain reaction (PCR) induced mutation restriction analysis (IMRA) were employed to detect lactoferrin gene polymorphism. RESULTS: All patients had had trichiasis at least for 1 year, and all amyloid-like deposits were found in one eye with trichiasis. Ophthalmological examination revealed that eight patients showed gelatinous type of amyloid deposition and one showed lattice type of amyloid deposition. Studies of biopsied corneal samples with Congo red stain revealed positive staining just under the corneal epithelial cells. Immunoreactivity of anti-human lactoferrin antibodies was recognised in all tissues with positive Congo red staining. Lactoferrin gene analysis revealed that seven patients were heterozygotic and two were homozygotic for lactoferrin Glu561Asp. The frequency of the polymorphism in the patients was significantly different from that in 56 healthy control subjects. CONCLUSION: Lactoferrin Glu561Asp is a key polymorphism related to facilitating amyloid formation in corneal amyloidosis with trichiasis.

Adolescent↗

PubMed1999

Decreased tear lactoferrin concentration in patients with chronic hepatitis C.

BACKGROUND/AIMS: Decreased tear volume in patients with chronic hepatitis C has been reported in the literature. Lactoferrin is abundantly present in human tears, the main source of which is the acini of the lacrimal glands. In this study tear lactoferrin levels were measured to investigate the dry eye condition of patients with chronic hepatitis C. METHODS: Lactoferrin in tears/fluid was measured by a radial immunodiffusion assay in 42 patients with chronic hepatitis C. The rate of lacrimal secretion was determined by the cotton thread test. Rose bengal staining of the ocular surface was also performed. RESULTS: Only three patients out of 42 complained of dry eye sensation and, in 31 patients, six showed positive results on the rose bengal staining test of the ocular surface. The lactoferrin concentration of tear fluid in the chronic hepatitis C group (1.42 (SD 0.56) mg/ml) was significantly lower than in the control group (1.90 (0.62) mg/ml; p <0.00048). The cotton thread test results in the chronic hepatitis C group (12.9 (5. 5) mm) were significantly lower than in the control group (17.9 (5. 3) mm; p<0.00048). Also, in the chronic hepatitis C group, tear lactoferrin concentration correlated with the results of the cotton thread test (r = 0.35, p<0.05). CONCLUSION: Chronic hepatitis C patients showed both decreased tear volume, and decreased tear lactoferrin concentration. These findings suggest that there may be dysfunction of the lacrimal glands in patients with chronic hepatitis C, which may account for the mild dry eye.

Adult↗

PubMed2002

Lactoferrin and host defense.

Lactoferrin is a multifunctional member of the transferrin family of nonheme iron-binding glycoproteins. Lactoferrin is found at the mucosal surface where it functions as a prominent component of the first line of host defense against infection and inflammation. The protein is also an abundant component of the specific granules of neutrophils and can be released into the serum upon neutrophil degranulation. While the iron-binding properties were originally believed to be solely responsible for the host defense properties ascribed to lactoferrin, it is now known that other mechanisms contribute to the broad spectrum anti-infective and anti-inflammatory roles of this protein. In this article, current information on the functions and mechanism of action of lactoferrin are reviewed, with particular emphasis on the activities that contribute to this protein's role in host defense. In addition, studies demonstrating that lactoferrin inhibits allergen-induced skin inflammation in both mice and humans, most likely secondary to TNF-alpha (tumor necrosis factor alpha) production, are summarized. Collectively, these results suggest that lactoferrin functions as a key component of mammalian host defense at the mucosal surface.

Animals↗

PubMed2002

Lactoferrin gene expression and regulation: an overview.

Lactoferrin is highly conserved among human, mouse, bovine, and porcine species. The numbers of amino acids encoded by 15 of the 17 exons in these species are identical, and in 12 locations, they have identical codon interruptions at the intron-exon splice junctions. However, lactoferrin expression is both ubiquitous and species, tissue, and cell-type specific. It is differentially regulated through multiple signaling pathways such as steroid hormone, growth factor, and kinase cascade pathways. Comparing the lactoferrin gene promoters from different species, common and different characteristics are observed. The human, mouse, bovine, porcine, and bubaline (African antelope) promoters all contain a noncanonical TATA box with an adjacent Sp1 site. Both human and mouse have multiple steroid hormone response elements, while none are found in the other species studied, suggesting that the lactoferrin gene is differentially regulated among different species by steroid hormones. Several transcription factors have been identified that are crucial for the expression of the lactoferrin gene during differentiation of the myeloid cells and in estrogen and epidermal growth factor regulation. This article provides an overview on lactoferrin expression and regulation in different species.

Amino Acid Sequence↗

PubMed2002

Lactoferrin-binding proteins in Bifidobacterium bifidum.

Lactoferrin is an iron-binding glycoprotein and its bacteriostatic and bactericidal effects on gram-positive and gram-negative bacteria are well known. On the other hand, it is known that certain kinds of lactic acid bacteria are resistant to its antibacterial effects. Moreover, it is reported that lactoferrin promotes the growth of bifidobacteria in in vitro and in vivo experiments. In our experiments, lactoferrin-binding protein was found both in the membrane and cytosolic fractions of Bifidobacterium bifidum Bb-11. The bifidobacteria were grown in anaerobic conditions with lactobacilli MRS broth containing cysteine, harvested by centrifugation, and processed by sonication. The lactoferrin-binding proteins on the PVDF-membrane transferred after SDS-PAGE were detected by far-Western (western-Western) method using biotinylated lactoferrin and streptavidin-labelled horse radish peroxidase. The molecular weights of the lactoferrin binding protein detected in the membrane fraction were estimated to be 69 kDa and those in cytosolic fractions were 20, 35, 50, and 66 kDa.

Animals↗

PubMed2006

Single nucleotide polymorphisms (SNPs) in human lactoferrin gene.

The lactoferrin protein possesses antimicrobial and antiviral activities. It is also involved in the modulation of the immune response. In a normal healthy individual, lactoferrin plays a role in the front-line host defense against infection and in immune and inflammatory responses. Whether genomic variations, such as single nucleotide polymorphisms (SNPs), have an effect on the structure and function of lactoferrin protein and whether these variations contribute to the different susceptibility of individuals in response to environmental insults are interesting health-related issues. In this study, the lactoferrin gene was resequenced as part of the Environmental Genome Project of the National Institute of Environmental Health Sciences, which operates within the National Institutes of Health. Ninety-one healthy donors of different ethnicities were used to establish common SNPs in the exons of the lactoferrin gene in the general population. The data will serve as a basis from which study the association of lactoferrin polymorphism and disease.

Ethnicity↗

PubMedDate not supplied

Lactoferrin inhibits growth of malignant tumors of the head and neck.

Lactoferrin, a naturally occurring glycoprotein found in breast milk, has previously been shown to have antimicrobial properties and recently has been demonstrated to inhibit malignant tumor growth, presumably through immunomodulation. We hypothesized that intratumoral injection of human and murine recombinant lactoferrin would decrease the growth of malignant tumors in vivo. Using an orthotopic murine model for both squamous cell carcinoma and fibrosarcoma of the floor of the mouth, we administered lactoferrin directly into the tumors using variable dosing strategies. Additionally, we performed in vitro experiments to assess whether the effects of lactoferrin are due to direct cytotoxicity. Our results revealed growth inhibition of 50% (p=0.03)and 54% (p=0.01) as compared with controls for both human and murine tumor cells in immunodeficient and immunocompetent mice, respectively. There was a more dramatic effect in immunocompetent models which may identify immunomodulation as an important mechanism of action for lactoferrin. Support for immunomodulation as a possible mechanism was the lack of any difference between controls and the experimental groups in vitro. Lactoferrin proved effective in reducing malignant tumor growth in a murine model. These properties offer hope for its use as a primary or adjuvant chemotherapeutic agent. Further investigation focused on mechanism and delivery is needed.

Animals↗

PubMed1976

Lactoferrin in human pancreas. Immunohistological localization in normal and pathological pancreatic tissues.

The protein composition of normal human pancreatic juice and pancreatic juice of men with chronic calcifying pancreatitis (CCP) were compared using immuno-diffusion techniques. An additional protein was found in pathological pancreatic juice and this protein has been identified as lactoferrin. Its concentration has been determined. The indirect immunofluorescence method was used to detect and localize lactoferrin in 9 samples of human pancreas from 3 patients with CCP and 6 patients without CCP. The fluorescence was found in all samples. Lactoferrin staining was localized in lumen acinar and in the cytoplasm of the acinar cells. The fluorescence was stronger in the apical zone of acinar cells. When lactoferrin antiserum was incubated with lactoferrin insolubilized by glutaraldehyde, no fluorescence staining was detected. The differences between our results obtained by immunodiffusion and immunofluorescence techniques are explained by the different sensitivity of the two techniques and these results indicate that lactoferrin is a protein of pancreatic secretion.

Chronic Disease↗

PubMed1995

Iron saturation alters the effect of lactoferrin on the proliferation and differentiation of human enterocytes (Caco-2 cells).

Recent studies have indicated that lactoferrin may act as a cell mitogen. The effect of human and bovine lactoferrins on the proliferation and differentiation of a human intestinal epithelial cell line (Caco-2) was investigated and compared with that of human transferrin. Caco-2 cells were cultured in serum-free media supplemented with both iron-unsaturated and -saturated forms of the iron-binding proteins. Cell proliferation and differentiation were evaluated by examining growth curves and measuring sucrase and alkaline phosphatase activities of brush border membrane fractions, respectively. The iron-binding status of lactoferrins and transferrin affected the proliferation of Caco-2 cells. The iron-saturated forms of human (S-hLf), bovine (S-bLf) lactoferrins and human transferrin (S-hTf) enhanced cell proliferation, while iron-unsaturated forms (U-hLf, U-bLf, and U-hTf) suppressed it. Iron-binding status also determined the effect of lactoferrin and transferrin on cellular differentiation, but this effect differed for different brush border enzymes. S-hTf enhanced sucrase activity more than S-hLF or S-bLf. Both U-hLf and U-bLf markedly suppressed sucrase activity. U-hTf suppressed alkaline phosphatase activity appreciably, while the other iron-binding proteins showed no significant effect on it. Lactoferrin and transferrin may modulate the proliferation and differentiation of intestinal epithelial cells, but their efficacy depends on their saturation with iron.

Animals↗

PubMed1997

Lactoferrin, a potent tryptase inhibitor, abolishes late-phase airway responses in allergic sheep.

Tryptase, a serine protease released exclusively from activated mast cells, has been implicated as a potential causative agent in asthma. Enzymatically active tryptase is comprised of four subunits, and heparin stabilizes the associated tetramer. Lactoferrin, a cationic protein released from activated neutrophils, binds tightly to heparin, therefore we investigated lactoferrin as an inhibitor of tryptase and found that it is both a potent (Ki' is 24 nM) and selective inhibitor. Size exclusion chromatography studies revealed that lactoferrin disrupted the quaternary structure of active tryptase. Lactoferrin was tested in an allergic sheep model of asthma; aerosolized lactoferrin (10 mg in 3 ml phosphate-buffered saline, 0.5 h before as well as 4 and 24 h after inhalation challenge by Ascaris suum) abolished both late-phase bronchoconstriction (no significant increase in specific lung resistance 4 to 8 h following provocation, p < 0.05 versus vehicle treatment) and airway hyperresponsiveness (no detectable increase in airway sensitivity to carbachol challenge 24 h after antigen challenge, p < 0.05 versus vehicle). These data suggest tryptase involvement in both late-phase bronchoconstriction and airway hyperreactivity and furthermore suggest that a physiological function of neutrophil lactoferrin is the inhibition of tryptase released from mast cells.

Airway Resistance↗

PubMed1989

Plasma lactoferrin levels in newborn preterm infants: effect of infection.

Plasma lactoferrin was measured within 24 h of birth in 23 preterm infants of between 24 and 36 weeks gestation. Lactoferrin concentrations fell with decreasing gestational age whilst the incidence of subsequent infection rose. Sequential measurements on a subgroup of 10 preterm infants showed that even when initial lactoferrin concentrations were within the range for term infants, they fell during the first week. Lactoferrin concentrations in preterm babies may rise transiently, such increases often being associated with clinical signs of infection. A rise in plasma lactoferrin of 200 micrograms/L or more over a period of less than 48 h is suggestive of infection. These findings are discussed in terms of both the possible role of lactoferrin, and the clinical usefulness of the measurement.

Gestational Age↗

PubMed1981

Lactoferrin: nuclear localization in the human neutrophilic granulocyte?

Conditions were established whereby nuclear or cytoplasmic immunocytochemical localization of lactoferrin was observed in the human peripheral blood granulocyte. A positive nuclear staining reaction was obtained when cells were either not fixed or treated with most fixatives. However, treatment of blood smears with formaldehydeacetone prior to the immunocytochemical localization gave a cytoplasmic staining reaction. A method was developed that allowed us to examine proteins obtained from granulocyte nuclei isolated from fixed cells. Only a trace amount of lactoferrin was detected in the electrophoretically separated nuclear proteins obtained from granulocytes treated for 1 min with formaldehyde-acetone. However, lactoferrin was major protein component in nuclei isolated from untreated cells, cells treated with other fixatives, or cells preincubated in buffered saline prior to formaldehyde-acetone fixation. formaldehyde-acetone treatment of nuclear materials containing lactoferrin did not extract lactoferrin or mask it from detection, thus indicating that lactoferrin found in the mature neutrophilic granulocyte nucleus is most likely acquired from other cellular organelles during tissue processing.

Cell Fractionation↗

PubMed2003

Seminal plasma lactoferrin but not transferrin reflects gonadal function in dogs.

Lactoferrin purified from canine seminal plasma by a three-step chromatography procedure had a molecular mass of 75.2 kDa and cross-reacted with antiserum to equine seminal plasma lactoferrin. Seminal plasma lactoferrin concentrations were determined by a competitive enzyme-linked immunosorbent assay (ELISA) by using rabbit anti-equine lactoferrin antibody and alkaline phosphatase-labeled goat anti-rabbit IgG antibody in 14 normal dogs and found to range from 12 to 197 micro g/ml, with a mean value of 77 +/- 59 micro g/ml (the mean +/- SD). Seminal plasma transferrin concentrations were determined by a sandwich ELISA with goat antibody to canine serum transferrin and alkaline phosphatase-conjugated goat anti-canine transferrin antibody and found to range from 0.32 to 12.6 micro g/m l, with a mean value of 2.44 +/- 3.25 micro g/m l. The lactoferrin concentration significantly correlated with the sperm concentration (r=0.7025, P<0.01), but there was no significant correlation between the seminal plasma transferrin concentration and sperm density. These results indicate that seminal plasma lactoferrin, but not transferrin, reflects gonadal function.

Animals↗

PubMed2001

Plasma total transcobalamin I. Ethnic/racial patterns and comparison with lactoferrin.

Plasma total transcobalamin (TC) I levels were measured in 434 healthy volunteers by radioimmunoassay (RIA). The results were analyzed for demographic patterns and were compared with lactoferrin, cobalamin, homocysteine, and chemistry panel results. Plasma TC I was higher in blacks than in other ethnic/racial groups and higher in women than in men. TC I levels did not correlate with lactoferrin levels. Lactoferrin showed significant ethnic differences also, but, unlike TC I, its levels were highest in whites. TC I levels correlated with cobalamin but not homocysteine levels. Neither TC I nor lactoferrin correlated with chemistry panel results, including creatinine, total protein, albumin, lactate dehydrogenase, and alkaline phosphatase levels. The demonstration with an RIA that directly measures total TC I that plasma levels are significantly higher in blacks than in other groups may explain the well-known higher cobalamin levels in blacks. Surprisingly, plasma lactoferrin, which has the same cellular sources as TC I, does not correlate with plasma TC I levels and shows dissimilar demographic patterns; lactoferrin levels are highest in whites. These findings suggest that regulation and/or secretion of these 2 proteins differ even though their localization and expression patterns in myeloid precursors are similar.

Adult↗

PubMed1999

Tissue and site-specific methylation correlates with expression of the mouse lactoferrin gene.

We have previously examined the regulatory region of the mouse lactoferrin gene and have identified sequences essential for basal and hormonally induced expression. In this study, we explore the relationship between the methylation state of the mouse lactoferrin gene promoter and its expression in selected mouse tissues. In a transient expression system, transcriptional activity was blocked after in vitro methylation of the regulatory region of the mouse lactoferrin gene. In addition, the in vivo methylation state of three promoter region sites was assessed using Southern blot analysis of DNA digested with methylation-insensitive and -sensitive restriction enzymes. The results showed that site -455, upstream of the mouse lactoferrin estrogen response module, was highly unmethylated in DNA from both hormone-treated and -untreated mouse lung, liver, and spleen tissues. Also, in both treated and untreated samples, the -54 site is uniquely highly unmethylated in liver DNA, while the -22 site is unmethylated in spleen DNA. Northern blot analysis showed lactoferrin expression in tissues that were unmethylated at a minimum of two sites. These results show that the alteration of the methylation status of the three sites are tissue-specific and are associated with constitutive expression of lactoferrin.

Animals↗

PubMed1989

Early fall of circulating iron and rapid rise of lactoferrin in septicemia and endotoxemia: an early defence mechanism.

Total serum iron, plasma lactoferrin and circulating leukocytes were measured in piglets during the early phase of severe gram-negative septicemia and endotoxemia in 3 experimental settings: intravenous (i.v.) infusion of lipopolysaccharide (LPS) (n = 8), i.v. infusion of live Escherichia coli (n = 7) and intraperitoneal (i.p.) infusion of E. coli (n = 6). Iron dropped significantly during the first 30 min of LPS infusion from a median of 32 microM to 13.4 microM. A similar decrease in serum iron was demonstrated in the 2 other groups with minimum values at 120 min after the start of E. coli infusion. Plasma levels of lactoferrin increased significantly 120 min after the start of LPS infusion (median 6 mg/l) when compared to preinfusion values (0.25 mg/l). After i.v. infusion of E. coli a significant rise of plasma lactoferrin was demonstrated already 30 min after bacterial infusion (to 2.1 mg/l) compared to preseptic values (0.8 mg/l). This increase was accompanied with a significant drop of circulating leukocytes (to 7.3 x 10(9)/l) compared to before the infusion (17 x 10(9)/l) in the pigs given E. coli i.v. After i.p. E. coli infusion no significant change of plasma lactoferrin was observed. The rapid fall of total serum iron seen during endotoxemia and E. coli septicemia may in part be explained by the release of lactoferrin from granulocytes and the clearance of iron-bound lactoferrin in the blood or peritoneal cavity.

Animals↗

PubMed1989

Two apparent molecular forms of bovine lactoferrin.

Bovine lactoferrin was prepared by CM-Sephadex column chromatography from defatted colostrum. When partially purified lactoferrin was analyzed by SDS-PAGE apparently two polypeptides of different size appeared. The polypeptides were transferred to a nitrocellulose sheet and visualized using antirabbit serum raised against the small polypeptide. Two polypeptides appeared clearly when stained by an immunological method. The color intensity of the two polypeptides was similar when the polypeptides were stained with Coomassie Brilliant Blue R-250. A high similarity of cyanogen bromide cleavage patterns between the two polypeptides was also observed in those stained with dye and immunologically visualized. Therefore, it is suggested that these polypeptides are lactoferrins. Comparison of the peptide patterns of the two lactoferrin molecules being deglycosylated suggested that sugar moieties may be one, but not all, of the causes of the size heterogeneity in lactoferrin. These results suggest that bovine colostrum contains two lactoferrin molecules of different size, although the physiological significance of the heterogeneity is not yet known.

Animals↗