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PubMed1992

Isolation of a lactoferrin cDNA clone and its expression in human breast cancer.

A cDNA library constructed from mRNA from a human breast carcinoma metastasis was screened with a polyclonal antibody to deglycosylated human milk fat globule membrane, resulting in the isolation of eight clones from a total of 10(5) plaques. One of these (J16) was identified as lactoferrin. It was highly expressed (as a 2.5 Kb mRNA) in lactating breast and in both normal resting tissue taken from adjacent to carcinoma or from reduction mammoplasties. Immunoreactive lactoferrin was localised to ductal cells and their secretions in both normal and mildly hyperplastic ducts. In a normal tissue screen J16 was highly expressed in stomach, poorly in skin and lymphocytes and absent from other organs examined. It was variably expressed in 33/59 invasive primary breast tumours; lactoferrin protein in these was heterogeneously distributed in epithelial tumour foci. Presence of J16 was inversely related to expression of oestrogen receptor protein (P = 0.0001). There was no significant relationship to other clinical parameters. We also found immunoreactivity in 20/41 (49%) cases of ductal carcinoma in situ. Expression was not observed in any breast or gastric cell line examined. Thus lactoferrin appears to be down regulated in some forms of cancer. The presence of lactoferrin could be a contraindication for effective endocrine therapy.

Biomarkers, Tumor↗

PubMed1992

Production of biologically active recombinant human lactoferrin in Aspergillus oryzae.

We report the production of recombinant human lactoferrin in Aspergillus oryzae. Expression of human lactoferrin (hLF), a 78 kD glycoprotein, was achieved by placing the cDNA under the control of the A. oryzae alpha-amylase promoter and the 3' flanking region of the A. niger glucoamylase gene. Using this system, hLF is expressed and secreted into the growth medium at levels up to 25 mg/l. The recombinant lactoferrin is indistinguishable from human milk lactoferrin with respect to its size, immunoreactivity, and iron-binding capacity. The recombinant protein appears to be appropriately N-linked glycosylated and correctly processed at the N-terminus by the A. oryzae secretory apparatus. Lactoferrin is the largest heterologous protein and the first mammalian glycoprotein expressed in the Aspergillus system to date. Hence, this expression system appears suitable for the large-scale production and secretion of biologically active mammalian glycoproteins.

Amino Acid Sequence↗

PubMed2003

Recombinant human lactoferrin ingestion attenuates indomethacin-induced enteropathy in vivo in healthy volunteers.

OBJECTIVE: To determine whether recombinant human lactoferrin ingestion inhibits nonsteroidal antiinflammatory drugs (NSAID)-induced gastroenteropathy in vivo in healthy volunteers as a model for disorders associated with a rise in permeability of the stomach and the small intestine. DESIGN: A randomized crossover dietary intervention. SUBJECTS AND INTERVENTIONS: In all, 15 healthy volunteers (age 23+/-1.4 y) were tested. A sucrose and a lactulose/rhamnose (L/R) permeability test was performed to assess gastroduodenal and small intestine permeability as indicator of NSAID-induced gastroenteropathy. All subjects consumed standardized meals for 2 days. On the second day at time=-24 h each subject ingested a drink containing 5 g recombinant human lactoferrin or placebo during breakfast. At t=-9 h, subjects ingested the same drink with 75 mg of the NSAID indomethacin and after an overnight fast at t=-1 h subjects consumed the drink and 50 mg indomethacin. After 1 h, at t=0, a permeability test was performed. RESULTS: Small intestine permeability after indomethacin and placebo was significantly higher (L/R ratio=0.036; 0.014-0.092, P<0.05) compared to the permeability observed after ingestion of indomethacin and lactoferrin (0.028; 0.015-0.056), whereas gastroduodenal permeability did not differ between the two interventions (P=0.3). CONCLUSION: Oral recombinant human lactoferrin supplementation during a short-term indomethacin challenge reduced the NSAID-mediated increase in small intestinal permeability and hence may provide a nutritional tool in the treatment of hyperpermeability-associated disorders. SPONSORSHIP: Grant and human recombinant lactoferrin donated from Agennix Inc., Houston, TX.

Administration, Oral↗

PubMed1998

Biliary lactoferrin concentrations are increased in active inflammatory bowel disease: a factor in the pathogenesis of primary sclerosing cholangitis?

1. One hypothesis for the link between inflammatory bowel disease and primary sclerosing cholangitis is that neutrophil activators, such as bacterial chemotactic peptides or neutrophil granule products themselves, pass from the inflamed colon to the liver via an enterohepatic circulation. However, there are no data on biliary concentrations of neutrophil granule products in patients with active and inactive inflammatory bowel disease.2. Gall bladder bile was obtained at laparotomy from 42 patients with ulcerative colitis and 21 patients with Crohn's disease. Biliary lactoferrin and myeloperoxidase concentrations were quantified by ELISA.3. In active ulcerative colitis, the mean lactoferrin concentration in gall bladder bile of 2.8+/-0.40 mg/l was higher than that seen after colectomy (1.2+/-0.11 mg/l; P<0.0001) or in patients with pouchitis (1.8+/-0.34 mg/l; P=0.06). In active Crohn's colitis, the mean lactoferrin concentration was 3.7+/-0.9 mg/l, compared with 1.1+/-0. 24 mg/l in the post-colectomy group (P<0.05) and 3.1+/-0.71 mg/l in those with active ileitis or ileocolitis. In contrast, biliary myeloperoxidase concentrations were low and comparable in all groups, with a mean concentration in the 42 patients with ulcerative colitis of 11.2+/-1.9 microgram/l.4. In contrast to myeloperoxidase, biliary lactoferrin concentrations are increased in active ulcerative colitis and Crohn's disease, and fall with colectomy and with disease remission. These findings indirectly support the hypothesis that bacterial chemotactic peptides (which induce selective degranulation of neutrophil secondary granules), and/or lactoferrin itself, undergo an enterohepatic circulation.

Acute Disease↗

PubMed1999

Influence of lactoferrin feeding and injection against systemic staphylococcal infections in mice.

Human and bovine lactoferrins (Lfs) and bovine lactoferrin hydrolysate (LH) were assessed in vitro and in vivo for their antibacterial effects on Staphylococcus aureus. Lactoferrins showed weak in vitro antibacterial activity while Fe-saturated Lfs and LH showed no activity. Lactoferrin-treated mice (1 mg, i.v.) when injected i.v. with 10(6) staphylococci, showed 30-50% reduction in kidney infections, and viable bacterial counts in the kidneys decreased 5-12-fold. The inhibitory effect was dose-dependent up to 1 mg Lf. Lactoferrins were effective when given 1 day prior to the bacterial challenge, after which there was no significant effect even at doses up to 5 mg. Apo- and Fe-saturated forms of human and bovine Lfs were all equally effective, while LH was not protective. Human and bovine Lfs with different degrees of iron saturation (9-97%) were found to be equipotent. Feeding mice with 2% bLf in drinking water also reduced the kidney infections by 40-60%, and viable bacterial counts, 5-12-fold. The results suggest a potential for the use of Lfs as natural antibacterial proteins for preventing bacterial infections.

Animals↗

PubMed1998

Transferrins--a mechanism for iron uptake by lactoferrin.

Iron uptake by bovine lactoferrin from nitrilotriacetatoFe(III) [FeN(Ac)3] in the presence of bicarbonate has been investigated at pH 7.1-8.7. Deprotonated apolactoferrin interacting with bicarbonate or carbonate extracts iron from nitrilotriacetatoFe(III); the direct second-order rate constant k1 = (4.90 +/- 0.20)x10(4) M(-1) s(-1), a reverse second-order rate constant k(-1) = (1.80+/-0.05)x10(5) M(-1) s(-1), and the iron-exchange equilibrium constant K1 = 0.25+/-0.05. The newly formed iron-protein complex loses a single proton with proton dissociation constant K3a = (17+/-0.5) nM, then undergoes a modification in its conformation followed by the loss of two or three protons; the first-order rate constant k2 = (1.0+/-0.10) s(-1). This induces a new modification in the conformation; the first-order rate constant k3 = (8.75+/-0.40)x10(-3) s(-1). This second modification in conformation controls the rate of iron uptake by the N site of the protein and is followed by a single proton loss; K5a = 8.0 nM. Finally, the holoprotein or the monoferric lactoferrin in their final equilibrated states are produced by a third modification in the conformation occurring in about 9000 s. The mechanism of iron uptake by lactoferrin is very similar to that of serum transferrin with a cooperativity between the C and N sites upon iron uptake but with lower rates, higher affinities and at least one more proton loss involved. These differences may be the result of slight discrepancies in the intimate structures of binding sites for serum transferrin and lactoferrin. In order to analyse the cooperativity between these iron-binding sites, the three-dimensional position of the chain of amino acid residues separating the N and C lobes of human apo-, holo- and dicopper-lactoferrin have been compared by the recognition of the three-dimensional shape dissimilarity program. The interlobe peptides of human hololactoferrin and apolactoferrin showed only 75.5 % tridimensional similarity, indicating that iron uptake affects the three-dimensional structure of the interlobe chain.

Animals↗

PubMed2000

Oral administration of bovine lactoferrin for treatment of tinea pedis. A placebo-controlled, double-blind study.

A clinical study was conducted to evaluate the effectiveness of lactoferrin, which is a protein component of cow's milk, in the treatment of tinea pedis. Doses of either 600 mg or 2000 mg of lactoferrin, or a placebo was orally administered daily for 8 weeks to 37 adults who were judged to have mild or moderate tinea pedis. Dermatological improvement and antifungal efficacy were assessed. In the analysis of all subjects, dermatological symptoms scores in all groups decreased but the differences were not statistically significant comparing the three groups. However, in the analysis limited to subjects with moderate vesicular or interdigital tinea pedis, dermatological symptoms scores in the lactoferrin-treated groups decreased significantly in comparison with the placebo group (P < 0.05). The organisms isolated were Trichophyton rubrum and Trichophyton mentagrophytes. A mycological cure was not seen in any of the subjects. In the 37 subjects there were no adverse events and no subject withdrew from the study because of an adverse event. These results suggest that orally administered lactoferrin can improve the dermatological symptoms in some subjects. The potential usefulness of lactoferrin as a functional food material for treating tinea pedis was seen for the first time in this study.

Administration, Oral↗

PubMed2000

Serum and milk lactoferrin concentration and the correlation with some blood components in lactating sows.

An increased serum concentration of lactoferrin is associated with inflammatory disease, but there are few reported data on this aspect for lactating sows. Samples of blood and milk were collected from 17 lactating sows under minimum stress conditions and analysed for lactoferrin. Lactoferrin concentrations in serum and milk were positively correlated, being high after farrowing and steadily decreasing throughout 28 days of lactation. A positive linear correlation was observed between lactoferrin concentration and enzyme activities of alanine aminotransferase, lactate dehydrogenase, and hydroxybutyrate dehydrogenase in the serum indicating post-partum inflammation. Serum and milk lactoferrin concentrations, although closely correlated, may be regulated through independent systems activated simultaneously.

Alanine Transaminase↗

PubMed2000

Effects of topical glucocorticoids on in vitro lactoferrin glandular secretion: comparison between human upper and lower airways.

BACKGROUND: Mucus hypersecretion is a hallmark of upper and lower airway diseases, such as rhinitis, asthma, and chronic obstructive pulmonary disease. Although topical glucocorticoids are widely used to treat mucosal inflammation, their effect on mucus hypersecretion remains uncertain. OBJECTIVE: The aim of this study was to investigate the effect of budesonide and beclomethasone dipropionate on in vitro lactoferrin glandular secretion from both human nasal and bronchial mucosa and the potential mediating role of lipocortin 1. METHODS: Nasal and bronchial explants obtained from patients undergoing surgery were cultured in a controlled atmosphere. Lactoferrin (ELISA) was measured in culture supernatants, and lipocortin 1 (Western blot) was analyzed in explant tissues. RESULTS: Both budesonide and beclomethasone dipropionate (10(-6) mol/L) decreased spontaneous lactoferrin secretion in nasal and bronchial mucosa. The maximum effect of cortico-steroids (10(-6) mol/L) was obtained at day 3 in bronchial mucosa (budesonide: -56% +/- 9%, P <.05; beclomethasone dipropionate: -32% +/- 6%, P <.05) and at day 5 in nasal mucosa (budesonide: -34% +/- 10%, P <.05; beclomethasone dipropionate: -37% +/- 10%, P <.05). Methacholine (10(-4) mol/L) increased lactoferrin secretion in both bronchial (248% +/- 72%, P <.05) and nasal (107% +/- 28%, P <.05) explants, with this effect being completely abrogated by atropine. Budesonide caused a dose-related inhibitory effect on methacholine-induced lactoferrin secretion that was similar in both bronchial (down to -86% at 10(-6) mol/L) and nasal (down to -73% at 10(-6) mol/L) mucosa. Budesonide (10(-6) mol/L) did not show any effect on lipocortin 1 expression. CONCLUSIONS: These results suggest that glucocorticoid effects on airway inflammation may include a reduction of mucus hypersecretion in both nasal and bronchial mucosa.

Administration, Topical↗

PubMed2000

Estrogen receptor-related receptor alpha 1 interacts with coactivator and constitutively activates the estrogen response elements of the human lactoferrin gene.

The human estrogen receptor-related receptor (ERRalpha1, NR3B1a) was shown to bind a steroidogenic factor binding element (SFRE), TCAAGGTCATC, 26 base pairs upstream from the estrogen response element (ERE) of the human lactoferrin gene promoter. A mutation made at SFRE significantly reduced estrogen-dependent transcription from the lactoferrin ERE in human endometrial cells. In this study, we demonstrated that ERRalpha1 binds both SFRE and ERE elements and constitutively transactivates the lactoferrin gene promoter. In DNase I footprinting protection analysis, both SFRE and ERE regions were protected by glutathione S-transferase-ERRalpha1 fusion protein. The receptor formed two protein-DNA complexes with either SFRE or ERE in electrophoresis mobility shift assay. Homodimerization of ERRalpha1 was confirmed with the mammalian two-hybrid system. ERRalpha1 activates reporter constructs containing various types of estrogen response elements in endometrial and non-endometrial cells in transient transfection experiments. Overexpressing the coactivator, SRC1a or GRIP1, further enhances ERRalpha1-induced transcriptional activity. We demonstrated that the AF2 domain of ERRalpha1 is essential for the transactivation function and that deletion or mutation at this region abrogates the activation capability. Protein-protein interaction between the SRC1a and ERRalpha1 C terminus was confirmed with a GST glutathione S-transferase "pull-down" assay. When comparing ERRalpha1 and the estrogen receptor alpha (ERalpha) in many of the experiments, we found that ERalpha can also bind SFRE of the lactoferrin gene and transactivate the promoter activity in a ligand-dependent manner. The present study demonstrated that ERRalpha1 binds similar DNA elements as ERalpha and confers its transactivation function constitutively. Therefore, ERRalpha1 may actively modulate the estrogen response of lactoferrin gene as well as other estrogen-responsive genes.

DNA Footprinting↗

PubMed2006

Crystal structure of the Tp34 (TP0971) lipoprotein of treponema pallidum: implications of its metal-bound state and affinity for human lactoferrin.

The Tp34 (TP0971) membrane lipoprotein of Treponema pallidum, an obligate human pathogen and the agent of syphilis, was previously reported to have lactoferrin binding properties. Given the non-cultivatable nature of T. pallidum, a structure-to-function approach was pursued to clarify further potential relationships between the Tp34 structural and biochemical properties and its propensity to bind human lactoferrin. The crystal structure of a nonacylated, recombinant form of Tp34 (rTp34), solved to a resolution of 1.9A(,) revealed two metaloccupied binding sites within a dimer; the identity of the ion most likely was zinc. Residues from both of the monomers contributed to the interfacial metal-binding sites; a novel feature was that the delta-sulfur of methionine coordinated the zinc ion. Analytical ultracentrifugation showed that, in solution, rTp34 formed a metal-stabilized dimer and that rTp34 bound human lactoferrin with a stoichiometry of 2:1. Isothermal titration calorimetry further revealed that rTp34 bound human lactoferrin at high (submicromolar) affinity. Finally, membrane topology studies revealed that native Tp34 is not located on the outer surface (outer membrane) of T. pallidum but, rather, is periplasmic. How propensity of Tp34 to bind zinc and the iron-sequestering lactoferrin may relate overall to the biology of T. pallidum infection in humans is discussed.

Crystallography, X-Ray↗

PubMed1997

Activation of macrophages by lactoferrin: secretion of TNF-alpha, IL-8 and NO.

When macrophages were cultured with lactoferrin, cytokines such as tumor necrosis factor (TNF-alpha), interleukin 8 (IL-8) and nitric oxide (NO) were secreted. Secretion of TNF-alpha peaked at 6 h of incubation in the presence of lactoferrin and then declined. About 80% of the maximum secretion of IL-8 was observed at 6 h of incubation. The concentration of IL-8 in the culture medium remained almost constant between 24-72 h. In contrast, no significant effect on NO secretion was observed at 6 h, but a significant effect was observed at 24 h and secretion gradually increased between 24-72 h. The effects of lactoferrin on the secretion of TNF-alpha, IL-8 and NO were dose-dependent and lactoferrin had a significant effect on secretion of at concentrations greater than 10 mg/ml. The use of reverse transcription-polymerase chain reaction (RT-PCR) showed that the results obtained were consistent with the cytokine secretion results. It is concluded that lactoferrin activates macrophages which result in the secretion of TNF-alpha, IL-8 and NO.

Animals↗

PubMed2001

Affinity enrichment of bovine lactoferrin in whey.

Bovine lactoferrin was enriched in various whey samples by affinity chromatography using immobilized gangliosides. Bovine gangliosides were isolated from fresh buttermilk using a combination of ultrafiltration and organic extraction. Isolated gangliosides were covalently immobilized onto controlled-pore glass beads. The immobilized matrix contained 66 micrograms of gangliosides per gram of beads. After loading the matrix with reconstituted whey protein isolate (WPI) or whey protein concentrate (WPC), the matrix was washed with sodium phosphate buffer (pH 7) followed by sodium acetate buffer (pH 4) before elution of lactoferrin with 1 M NaCl in sodium acetate buffer. From the intensities of the protein bands in SDS-PAGE, lactoferrin constituted a minimum of 40% of the total protein in the salt eluted sample. WPI, pretrated by heating and ultrafiltration, showed the highest lactoferrin purity among protein sources, while WPI (10% wt/vol) showed the highest recovery. These results show that immobilized gangliosides can be used to enrich the lactoferrin content of whey.

Animals↗

PubMed2004

Loss of microbicidal activity and increased formation of biofilm due to decreased lactoferrin activity in patients with cystic fibrosis.

Intractable formation of biofilm by and infection with the opportunistic pathogen Pseudomonas aeruginosa are hallmarks of cystic fibrosis (CF). Lactoferrin, an innate immunity protein, has recently been shown to inhibit the formation of P. aeruginosa biofilm. Partial cleavage of lactoferrin by the proteases neutrophil elastase and Pseudomonas elastase has previously been described in CF. Here, we show that cathepsins in CF secretions are responsible for complete and rapid cleavage of lactoferrin. We demonstrate that levels of lactoferrin in P. aeruginosa-positive sputum samples are decreased when corrected for inflammatory burden and that P. aeruginosa-positive sputum samples have significantly higher cathepsin activity and significantly reduced ability to inhibit formation of biofilm, compared with P. aeruginosa-negative sputum samples. We also show that cleavage of lactoferrin by cathepsin results in loss of both its microbicidal and antibiofilm activity. Loss of such a vital innate immunity protein clearly has important implications for the pathogenesis of chronic P. aeruginosa lung infection in patients with CF.

Adolescent↗

PubMed1988

Neutrophil lactoferrin content in viral infections.

In an attempt to elucidate the previously observed decrease in plasma lactoferrin-neutrophil ratio in subjects with acute viral infections, a study of the neutrophil lactoferrin content in such infections was undertaken. With the use of an immunoperoxidase stain for lactoferrin, neutrophils in viral illness were shown to have reduced lactoferrin content (mean score 97.9 +/- SD [38.0] per 100 neutrophils) as compared with normal subjects (mean score 196.4 +/- SD [3.6] per 100 neutrophils) (t = 7.69; P less than 0.0005). This suggests an acquired defect of neutrophil lactoferrin synthesis in viral infection. This finding is of importance when seen against the well-recognized increased risk of bacterial superinfection in subjects who have recently had a viral infection.

Adult↗

PubMed2000

Inhibition of growth of Pneumocystis carinii by lactoferrins alone and in combination with pyrimethamine, clarithromycin and minocycline.

The in vitro activity of lactoferrins alone and in combination with clarithromycin, minocycline and pyrimethamine was investigated against three clinical isolates of Pneumocystis carinii. Susceptibility was tested by inoculating isolates on to cell monolayers and determining the parasite count after 72 h incubation at 37 degrees C. The culture medium was supplemented with serial dilutions of each agent. At 20 mg/L, bovine lactoferrin, the most active agent, suppressed the growth of cystic and trophic forms by >60%. Human lactoferrin, at the same concentration, suppressed the growth of cystic and trophic forms by >50%. Lactoferrins at 20 mg/L combined with clarithromycin 4 mg/L had high anti-P. carinii activity, with a >90% decrease in cystic and trophic form counts. Our study suggests that lactoferrins may inhibit P. carinii growth in vitro and act synergically with other clinically used compounds. These findings lend experimental support to the use of iron-chelating agents in the therapy of pneumocystis infections.

Animals↗

PubMedDate not supplied

Use of lactoferrin for Helicobacter pylori eradication. Preliminary results.

BACKGROUND: One-week triple therapy is the most frequently recommended treatment of Helicobacter pylori infection. The associated eradication rate is satisfactory; nevertheless, it is advisable to look for more effective therapies. Our aim was to test the efficacy of a standard triple therapy plus bovine lactoferrin for the eradication of H. pylori infection. STUDY: This open, randomized, single-center study was designed to include 150 consecutive H. pylori-positive patients with dyspeptic symptoms and gastritis who received triple therapy with rabeprazole, clarithromycin, and tinidazole plus lactoferrin for 7 days (group A), rabeprazole, clarithromycin, and tinidazole for 7 days (group B), or rabeprazole, clarithromycin, and tinidazole for 10 days (group C). H. pylori status was assessed 8 weeks after the end of treatment by means of the 13C-urea breath test or H. pylori stool antigen test. RESULTS: The 7-day treatment including lactoferrin (group A) was successful in 100% (24/24) of the patients. The eradication rates in groups B and C were 76.9% (20/26 patients; 95% CI, 61%-93%) and 70.8% (17/24 patients; 95% CI, 53%-89%), respectively. A significant difference was found between group A and group B (P = 0.023) and group A and group C (P = 0.022). No differences were found between group B and group C (P = 1.00). CONCLUSION: These results suggest that lactoferrin could be a new, effective agent when added to antimicrobial therapy for the eradication of H. pylori. This treatment schedule could be proposed for larger trials of H. pylori eradication therapy, focusing on the excellent preliminary cure rate, good compliance to the treatment schedule, and relatively low price of lactoferrin for full treatment.

Drug Therapy, Combination↗

PubMed1985

Breast milk lactoferrin levels in relation to maternal nutritional status.

Lactoferrin was measured in breast milk from Aboriginal and non-Aboriginal Australian women using an enzyme immunoassay. There was no diurnal variation in lactoferrin concentration or change in concentration between the beginning and end of a feed. Lactoferrin levels were significantly higher in the first 15 days postpartum than in the period after the 15th day. Regression analysis showed that in milk from Aboriginal women less than 15 days postpartum, higher concentrations of lactoferrin were associated with weight for height (WFH) greater than 90% and with increased parity. Comparable data were not available for Caucasian women. For Aboriginal and Caucasian women more than 15 days postpartum, lactoferrin concentrations were higher in women greater than 90% WFH. Other variables, such as parity, were not significant in the regression.

Adult↗