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PubMed2003

In vitro characterization of lactoferrin aggregation and amyloid formation.

Lactoferrin has previously been identified in amyloid deposits in the cornea, seminal vesicles, and brain. We report in this paper a highly amyloidogenic region of lactoferrin (sequence of NAGDVAFV). This region was initially identified by sequence comparison with medin, a 5.5 kDa amyloidogenic fragment derived from lactadherin. Subsequent characterization revealed that this peptide forms amyloid fibrils at pH 7.4 when incubated at 37 degrees C. Furthermore, although full-length lactoferrin does not by itself form amyloid fibrils, the protein does bind to the peptide fibrils as revealed by an increase in thioflavin T fluorescence and the presence of enlarged fibrils by transmission electron microscopy and polarized light microscopy. The binding of lactoferrin is a selective interaction with the NAGDVAFV fibrils. Lactoferrin does not bind to insulin or lysozyme fibrils, and the NAGDVAFV fibrils do not bind to soluble insulin or lysozyme. The lactoferrin appears to coat the peptide fibril surface to form mixed peptide/protein fibrils, but again there is no evidence for the formation of lactoferrin-only fibrils. This interaction, therefore, seems to involve selective binding rather than conventional seeding of fibril formation. We suggest that such a process could be generally important in the formation of amyloid fibrils in vivo since the identification of both full-length protein and protein fragments is common in ex vivo amyloid deposits.

Amino Acid Sequence↗

PubMed2000

Lactoferrin protects gut mucosal integrity during endotoxemia induced by lipopolysaccharide in mice.

The hypothesis that lactoferrin protects mice against lethal effects of bacterial lipopolysaccharide (LPS) is the subject of experimental investigations described in this article. Lipopolysaccharide is a powerful toxin produced by gram negative bacteria that when injected into humans or experimental animals reproduce many of the pathophysiologic and immune responses caused by live bacteria. Lactoferrin administered intraperitoneally 1 hr prior to injection of LPS significantly enhanced the survival of mice, reducing LPS-induced mortality from 83.3% to 16.7%. Changes in locomotor and other behavioral activities resulting from LPS injection were not present in mice treated with lactoferrin. Also, histological examination of intestine revealed remarkable resistance to injury produced by LPS if mice were pretreated with lactoferrin. Severe villus atrophy, edema and epithelial vacuolation were observed in LPS-treated animals but not in lactoferrin-treated counterparts. Electrophysiological parameters were used to assess secretory and absorptive functions in the small intestine. In mice treated with LPS, transmural electrical resistance was reduced and absorption of glucose was increased. Lactoferrin treatment had no significant influence on basal electrophysiological correlates of net ion secretion or glucose absorption nor on changes induced by LPS. Collectively, these results suggest that lactoferrin attenuates the lethal effect of LPS and modulates behavioral and histopathological sequela of endotoxemia.

Animals↗

PubMed2004

Proteolytic activity of bovine lactoferrin.

Bovine lactoferrin catalyzes the hydrolysis of synthetic substrates (i.e., Z-aminoacyl-7-amido-4-methylcoumarin). Values of Km and kcat for the bovine lactoferrin catalyzed hydrolysis of Z-Phe-Arg-7-amido-4-methylcoumarin are 50 microM and 0.03 s(-1), respectively, the optimum pH value is 7.5 at 25 degrees C. The bovine lactoferrin substrate specificity is similar to that of trypsin, while the hydrolysis rate is several orders of magnitude lower than that of trypsin. The bovine lactoferrin catalytic activity is irreversibly inhibited by the serine-protease inhibitors PMSF and Pefabloc. Moreover, both iron-saturation of the protein and LPS addition strongly inhibit the bovine lactoferrin activity. Interestingly, bovine lactoferrin undergoes partial auto-proteolytic cleavage at positions Arg415-Lys416 and Lys440-Lys441. pKa shift calculations indicate that several Ser residues of bovine lactoferrin display the high nucleophilicity required to potentially catalyze substrate cleavage. However, a definitive identification of the active site awaits further studies.

Animals↗

PubMed1993

The developmental profile of lactoferrin in mouse epididymis.

A sandwich e.l.i.s.a. method was developed to examine the distribution of lactoferrin in mouse reproductive tract. The lactoferrin concentration was found to be much higher in oviduct, uterus, vagina, vas deferens or epididymis than in serum, but the concentration in ovary, testis, seminal vesicle, prostate or coagulating gland was comparable with that in serum. The existence of lactoferrin in male sexual organs was confirmed by Western-blot analyses for tissue proteins. Lactoferrin in male sexual organs was shown to have a molecular mass similar to that of the deglycosylated form of lactoferrin purified from mouse uterine luminal fluid. Northern-blot analyses for total RNA prepared from male sexual organs indicated that only epididymis contained the lactoferrin mRNA. The lactoferrin mRNA was found in the prepubertal period and increased with the growth of epididymis. The mRNA level in prepubertal epididymis could be stimulated by 17 beta-oestradiol, but was not influenced by testosterone.

Aging↗

PubMed2003

Human recombinant lactoferrin is ineffective in the treatment of human Helicobacter pylori infection.

BACKGROUND: Lactoferrin, a multifunctional glycoprotein, is known to have anti-microbial actions. Bovine lactoferrin and recombinant human lactoferrin have been shown to inhibit Helicobacter pylori, and more recently recombinant human lactoferrin was found to significantly increase the eradication rate of H. pylori when added to standard triple therapy. AIM: To determine the efficacy, safety and tolerability of recombinant human lactoferrin as a therapy in suppressing or eliminating H. pylori infection in subjects with minimal upper gastrointestinal symptoms who have not previously been treated. SUBJECTS AND METHODS: Nine healthy subjects with minimal upper gastrointestinal symptoms and a positive urea breath test were recruited. None of the volunteers had previously been treated for H. pylori. Subjects received 5 x 1.0 g human recombinant lactoferrin daily for 5 or 14 days. Breath tests were repeated during therapy and shortly after to check for eradication. The safety and tolerability of the drug were assessed by physical examination, by monitoring adverse events, and clinical laboratory evaluation. RESULTS: No conversion of the urea breath test from positive to negative was observed and there was no consistent change in urea breath test count to indicate a possible suppression of H. pylori. CONCLUSION: Lactoferrin, given as a single agent, does not eradicate H. pylori infection.

Adult↗

PubMed2002

Differential effects of prophylactic, concurrent and therapeutic lactoferrin treatment on LPS-induced inflammatory responses in mice.

Mice injected with endotoxin develop endotoxaemia and endotoxin-induced death, accompanied by the oxidative burst and overproduction of inflammatory mediators. Lactoferrin, an iron binding protein, provides a natural feedback mechanism to control the development of such metabolic imbalance and protects against deleterious effects of endotoxin. We investigated the effects of intraperitoneal administration of human lactoferrin on lipopolysaccharide (LPS)-induced release of tumour necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), interleukin 10 (IL-10) and nitric oxide (NO) in vivo. Lactoferrin was administered as a prophylactic, concurrent or therapeutic event relative to endotoxic shock by intravenous injection of LPS. Inflammatory mediators were measured in serum at 2, 6 and 18 h post-shock induction. Administration of lactoferrin 1 h before LPS resulted in a rather uniform inhibition of all mediators; TNF by 82%, IL-6 by 43%, IL-10 by 47% at 2 h following LPS injection,and reduction in NO (80%) at 6 h post-shock. Prophylactic administration of lactoferrin at 18 h prior to LPS injection resulted in similar decreases in TNF-alpha (95%) and in NO (62%), but no statistical reduction in IL-6 or IL-10. Similarly, when lactoferrin was administered as a therapeutic post-induction of endotoxic shock, significant reductions were apparent in TNF-alpha and NO in serum, but no significant effect was seen on IL-6 and IL-10. These results suggest that the mechanism of action for lactoferrin contains a component for differential regulation of cellular immune responses during in vivo models of sepsis.

Animals↗

PubMed2003

Human milk lactoferrin is a serine protease that cleaves Haemophilus surface proteins at arginine-rich sites.

Lactoferrin is a member of the lactotransferrin family of non-haem, iron-binding glycoproteins and is found at high concentrations in all human secretions, where it plays a major role in mucosal defence. In recent work, we observed that lactoferrin has proteolytic activity and attenuates the pathogenic potential of Haemophilus influenzae by cleaving and removing two putative colonization factors, namely the IgA1 protease protein and the Hap adhesin. Experiments with protease inhibitors further suggested that lactoferrin may belong to a serine protease family. In the present study we explored the mechanism of lactoferrin protease activity and discovered that mutation of either Ser259 or Lys73 results in a dramatic decrease in proteolysis. Examination of the crystal structure revealed that these two residues are located in the N-terminal lobe of the protein, adjacent to a 12-15 A cleft that separates the N-lobe and the C-lobe and that can readily accommodate large polypeptide substrates. In additional work, we found that lactoferrin cleaves IgA1 protease at an arginine-rich region defined by amino acids 1379-1386 (RRSRRSVR) and digests Hap at an arginine-rich sequence between amino acids 1016 and 1023 (VRSRRAAR). Based on our results, we conclude that lactoferrin is a serine protease capable of cleaving arginine-rich sequences. We speculate that Ser259 and Lys73 form a catalytic dyad, reminiscent of a number of bacterial serine proteases. In addition, we speculate that lactoferrin may cleave arginine-rich sequences in a variety of microbial virulence proteins, contributing to its long-recognized antimicrobial properties.

Amino Acid Sequence↗

PubMed2005

[Muramidase and lactoferrin in adenoidal hypertrophies, hypertrophic and chronic infected tonsil tissue--a quantitative analysis].

BACKGROUND: Muramidase and lactoferrin are important components of the antimicrobial defense system. Muramidase has the ability of opsonization and immunopotentiation and therefore a close relation to the lymphatic tissue. Till now there are only immunohistochemical and microbiological studies on the presence of muramidase and lactoferrin in adenoid and tonsil tissue available. METHOD: We investigated the concentrations of muramidase and lactoferrin in palatine tonsils and adenoidal hypertrophies quantitatively using ELISA. MATERIAL: We investigated tissue of 18 palatine tonsils and 16 pharyngeal tonsils. RESULTS: We found a significant difference in the concentration of muramidase but no difference in the concentration of lactoferrin between adenoids and tonsils. There was no significant difference in the concentration of lactoferrin and muramidase between the hypertrophic and chronic infected tonsils. There was no correlation between the age of the patients and the concentration of muramidase and lactoferrin. A connection between the microbial biofilm, the concentration of the proteins and the recurrent tonsillitis is discussed. CONCLUSIONS: Due to the production of muramidase and lactoferrin adenoids and tonsils play an important role in the local antimicrobial defense in any age or inflammation.

Adenoids↗

PubMed1998

Human milk lactoferrin inactivates two putative colonization factors expressed by Haemophilus influenzae.

Haemophilus influenzae is a major cause of otitis media and other respiratory tract disease in children. The pathogenesis of disease begins with colonization of the upper respiratory mucosa, a process that involves evasion of local immune mechanisms and adherence to epithelial cells. Several studies have demonstrated that human milk is protective against H. influenzae colonization and disease. In the present study, we examined the effect of human milk on the H. influenzae IgA1 protease and Hap adhesin, two autotransported proteins that are presumed to facilitate colonization. Our results demonstrated that human milk lactoferrin efficiently extracted the IgA1 protease preprotein from the bacterial outer membrane. In addition, lactoferrin specifically degraded the Hap adhesin and abolished Hap-mediated adherence. Extraction of IgA1 protease and degradation of Hap were localized to the N-lobe of the bilobed lactoferrin molecule and were inhibited by serine protease inhibitors, suggesting that the lactoferrin N-lobe may contain serine protease activity. Additional experiments revealed no effect of lactoferrin on the H. influenzae P2, P5, and P6 outer-membrane proteins, which are distinguished from IgA1 protease and Hap by the lack of an N-terminal passenger domain or an extracellular linker region. These results suggest that human milk lactoferrin may attenuate the pathogenic potential of H. influenzae by selectively inactivating IgA1 protease and Hap, thereby interfering with colonization. Future studies should examine the therapeutic potential of lactoferrin, perhaps as a supplement in infant formulas.

Adhesins, Bacterial↗

PubMed1999

Lactoferrin increases the susceptibility of S. epidermidis biofilms to lysozyme and vancomycin.

PURPOSE: The tear cationic protein lactoferrin increases the activity of various antimicrobial agents against suspended bacterial cultures including Staphylococcus epidermidis, the predominant causative agent of intraocular lens biofilm infections. We investigated the ability of lactoferrin to enhance the activity of vancomycin and lysozyme against biofilms of a clinical S. epidermidis isolate. METHODS: Biofilms were prepared on soft contact lenses and cells released from the biofilm surface were collected from the surrounding broth. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against the intact biofilm, released cells and suspended bacteria were evaluated using vancomycin with and without lactoferrin. RESULTS: Lactoferrin induced a two-fold reduction in the MBC of vancomycin for biofilm (p < 0.01) and biofilm-released cells from 64 microg/ml to 32 microg/ml and similarly decreased the MIC for biofilm-released cells (p < 0.01) from 32 microg/ml to 16 microg/ml. With or without lactoferrin, the MIC of vancomycin for suspended cells (2 and 4 microg/ml respectively) was less (p < 0.01) than that of both the biofilm (32 and 32 microg/ml) and biofilm-released cells (16 and 32 microg/ml). Lactoferrin did not reduce the MIC of lysozyme, but, at a lysozyme concentration of 16 mg/ml, did significantly (p < 0.05) reduce the number of viable biofilm and biofilm-released cells. CONCLUSIONS: Lactoferrin displays potential as an adjunctive agent to vancomycin in the treatment of S. epidermidis biofilm infections, such as endophthalmitis, associated with intraocular lenses.

Anti-Bacterial Agents↗

PubMed2002

Human lactoferrin impairs virulence of Shigella flexneri.

Lactoferrin is a glycoprotein present in most human mucosal secretions, including human milk. Lactoferrin is bacteriostatic in low iron media and, in some settings, bactericidal. Lactoferrin impairs ability of Shigella flexneri serotype 5 strain M90T to invade HeLa cells. To determine the mechanism by which lactoferrin decreases invasiveness of Shigella organisms, its effect on the major virulence proteins responsible for bacterial uptake by host cells was evaluated. Lactoferrin induced degradation of invasion plasmid antigens IpaB and, to a lesser extent, IpaC, the key proteins responsible for bacteria-directed phagocytosis by mammalian cells. The lipid A-binding N-terminal portion of lactoferrin (residues 1-33) induces release of invasion antigens but does not induce degradation of IpaBC. Lactoferrin does not directly degrade previously released invasion plasmid antigens but works by making IpaBC susceptible to breakdown by surface-expressed protease(s).

Antigens, Bacterial↗

PubMed1998

Lactoferrin suppresses loss of corneal epithelial integrity in a rabbit short-term dry eye model.

Human tear fluid contains lactoferrin at the highest concentration. In patients with dry eye such as Sjogren's syndrome, the concentration of lactoferrin in the tears is approximately half the normal value. The present study utilizes a short-term rabbit dry eye model to evaluate if lactoferrin containing eye drops can reverse any of the damage produced by blockage of blinking with an ocular speculum. Damage was evaluated based on the extent of methylene blue staining in histological sections. After 3 h of desiccation, the amount of extractable dye recovered following sacrifice increased by more than 4-fold in the vehicle-treated eyes. However, in those rabbits treated with 1% lactoferrin, dye recovery was only 40% of the value in the vehicle-treated eyes. Between 1-3 h and over a concentration range from 0.01 to 1% lactoferrin, the decreases in staining were both time and concentration dependent. Alternatively, if 1% lactoferrin was applied during the desiccation period, there was partial restoration of corneal epithelial integrity. These results suggest that lactoferrin may be of therapeutic value in decreasing the loss of corneal epithelial integrity in dry eye.

Animals↗

PubMed2000

Lactoferrin given in food facilitates dermatophytosis cure in guinea pig models.

Dermatophytosis is the most common skin infection caused by dermatophytic fungi, such as Trichophyton spp. We studied the in vitro and in vivo antifungal effects of lactoferrin against Trichophyton. Human and bovine lactoferrin, and a bovine lactoferrin-derived peptide, lactoferricin B, showed in vitro antifungal activity that was dependent on the test strain and medium used. In guinea pigs infected on the back with Trichophyton mentagrophytes (i.e. those with tinea corporis), consecutive daily po administration of bovine lactoferrin did not prevent development of symptoms during the early phase of infection, but facilitated clinical improvement of skin lesions after the peak of the symptoms. The fungal burden in lesions was less in guinea pigs that had been given lactoferrin than in untreated controls 21 days after infection. In guinea pigs infected on the foot with T. mentagrophytes (i.e. those with tinea pedis), the fungal burden of the skin on the heel portion of the infected foot 35 days after infection was lower in animals fed lactoferrin than in controls. These results suggest the potential usefulness of lactoferrin as a food component for promoting dermatophytosis cure.

Administration, Oral↗

PubMed2001

Functional fragments of ingested lactoferrin are resistant to proteolytic degradation in the gastrointestinal tract of adult rats.

Pharmaceutical and food-related applications of lactoferrin, an 80-kDa iron-binding glycoprotein found predominantly in milk, have attracted interest lately, but the process of digestion of lactoferrin has been poorly characterized. The digestive fate of bovine lactoferrin in adult rats after oral administration of a single dose and after dietary supplementation was studied by (125)I-labeling and by surface-enhanced laser desorption/ionization (SELDI) affinity mass spectrometry. The latter method was designed to detect multiple forms of degraded lactoferrin as simple molecular ion peaks corresponding to one of the core regions of lactoferrin, namely, the lactoferricin region (Phe17-Ala42). Radioactive fragments with molecular masses of 42, 36, 33 and 29 kDa were observed at 20, 60 and 180 min postingestion in the contents of the lower small intestine. Rats were given free access to milk enriched with lactoferrin at 482 micromol/L (40 mg/mL). The concentrations of lactoferrin fragments in the contents of the stomach, small intestine and lower small intestine as determined by SELDI affinity mass spectrometry were approximately 200, 20 and 1 micromol/L, respectively. These data indicate that functional fragments of LF such as fragments containing glycosaminoglycan-binding site(s), as well as large fragments with a mass >20 kDa, indeed survive proteolytic degradation in the small intestine of adult rats.

Administration, Oral↗

PubMed2002

Lactoferrin gene expression is estrogen responsive in human and rhesus monkey endometrium.

We have previously shown that the estrogen responsiveness of the human lactoferrin gene in a transient transfection system is mediated through an imperfect estrogen response element (ERE) and a steroidogenic factor 1 binding element (SFRE) 26 bp upstream from ERE. Reporter constructs containing SFRE and ERE respond to estrogen stimulation in a dose-dependent manner, whereas mutations at either one of the response elements severely impaired the estrogen responsiveness. In this study, we demonstrated that estrogen receptor (ERalpha) binds to the human lactoferrin gene ERE and forms two complexes in an electrophoresis mobility shift assay (EMSA). These complexes could be supershifted by an antibody to ERalpha. We also showed that in normal cycling women, lactoferrin gene expression in the endometrium increases during the proliferative phase and diminishes during the luteal phase. This in-vivo study thus supported the finding from transient transfection experiments that the human lactoferrin gene expression is elevated in an environment with a high level of estrogen. The estrogen effect on lactoferrin gene expression in the rhesus monkey endometrium was studied by Western blotting and immunohistochemistry. The immunohistochemistry results showed that immunoreactive lactoferrin protein was not detectable in the untreated ovariectomized monkey endometrium, was elevated by estrogen treatment, and was suppressed by sequential, combined estrogen plus progesterone treatment. In conclusion, this study has shown that lactoferrin gene expression is responsive to estrogen in primate endometrium.

Adult↗

PubMed1992

Cytidine deaminase and lactoferrin in inflammatory synovial fluids. Indicators of local polymorphonuclear cell function?

Cytidine deaminase (CD) is a cytoplasmatic enzyme present predominantly in polymorphonuclear cells (PMNC) in inflamed joints. Lactoferrin is situated in the secondary granules of PMNC and is released by secretory/phagocytic stimuli, whereas CD is released mainly upon cell lysis. To study the release of these molecules in arthritic conditions we measured CD and lactoferrin levels in synovial fluid (SF) drawn from patients with rheumatoid arthritis (RA), crystal pyrophosphate disease (CPPD), psoriatic arthropathy, reactive arthritis, spondylarthropathy, and osteoarthrosis. CD activity was highest in SF from RA and CPPD followed by psoriatic arthropathy, reactive arthritis and spondylarthropathy. Lactoferrin concentrations were highest in CPPD followed by RA, reactive arthritis, psoriatic arthropathy, and spondylarthropathy. Both CD and lactoferrin levels were low in osteoarthrosis SF. Although SF CD activity and lactoferrin levels correlated well in all diagnostic groups, the ratio between CD and lactoferrin was higher for RA, psoriatic arthropathy, and spondylarthropathy compared to reactive arthritis and CPPD. This suggests predominant release by PMNC lysis in the more chronic arthritis groups and more degranulation in the more episodic CPPD and reactive arthritis groups. CD activity and lactoferrin levels correlated significantly with SF cell counts in the RA and psoriatic arthropathy groups.

Arthritis, Psoriatic↗

PubMed2000

Paracrine regulation of epithelial progesterone receptor and lactoferrin by progesterone in the mouse uterus.

The objective of this study was to determine whether uterine stromal and/or epithelial progesterone receptor (PR) is required for the antagonism by progesterone (P(4)) of estradiol-17beta (E(2)) action on expression of PR and lactoferrin in uterine epithelium. Uterine tissue recombinants were prepared with epithelium (E) and stroma (S) from wild-type (wt) and PR knockout (PRKO) mice: wt-S+wt-E and PRKO-S+wt-E. P(4) action on epithelial PR expression was studied in wt-S+wt-E and PRKO-S+wt-E tissue recombinants. E(2) down-regulated epithelial PR in both types of tissue recombinants, but P(4) blocked E(2)-induced down-regulation of epithelial PR only in wt-S+wt-E tissue recombinants. Thus, P(4) requires stromal PR to inhibit E(2)-induced down-regulation of epithelial PR. Epithelial PR is not sufficient in itself. The inhibitory effect of P(4) on lactoferrin expression was studied in 4 types of tissue recombinants (wt-S+wt-E, PRKO-S+wt-E, wt-S+PRKO-E, and PRKO-S+PRKO-E). E(2) induced lactoferrin in all 4 types of tissue recombinants. P(4) blocked E(2)-induced lactoferrin expression only in wt-S+wt-E tissue recombinants. In wt-S+PRKO-E tissue recombinants, P(4) inhibited lactoferrin expression only partially. P(4) failed to block E(2)-induced lactoferrin expression in PRKO-S+wt-E and PRKO-S+PRKO-E tissue recombinants. Thus, both epithelial and stromal PR are essential for full P(4) inhibition of E(2)-induced lactoferrin expression.

Animals↗

PubMed2000

Lactoferrin protects against UV-B irradiation-induced corneal epithelial damage in rats.

PURPOSE: Lactoferrin supplementation suppresses ultraviolet light B (UV-B)-induced oxidation of cultures of human corneal epithelial cells. To investigate the protective effect of lactoferrin containing eyedrops against UV-B-induced corneal damage in vivo, we examined lactoferrin efficacy in a rat UV-B keratitis model. METHODS: Sprague-Dawley rats were irradiated with >10 kJ/m2 after anesthetization, and then corneal epithelial defect was observed at 24 h postirradiation. The pre- or postapplication of vehicle or lactoferrin-containing eyedrops was performed, and then corneal epithelial damage was scored based on fluorescein staining. RESULTS: Posttreatment with lactoferrin did not inhibit the extent of corneal damage and did not affect wound healing. However, pretreatment by topical application of lactoferrin suppressed development of a corneal epithelial defect induced by UV-B irradiation in rats. CONCLUSION: These results suggest that the presence of lactoferrin in human tear fluid may inhibit UV-induced corneal epithelial damage.

Animals↗