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PubMed2006

Bovine lactoferrin inhibits echovirus endocytic pathway by interacting with viral structural polypeptides.

Lactoferrin, an 80 kDa bi-globular iron-binding glycoprotein belonging to the transferrin family, is a pleiotropic factor with potent antimicrobial and immunomodulatory activities, present in breast milk, in mucosal secretions, and in the secondary granules of neutrophils. Recently, we have shown that bovine lactoferrin prevents the early phases of echovirus infection and also acts as a survival factor inhibiting viral-induced apoptosis. In the present research we investigated the mechanism of bovine lactoferrin anti-echoviral effect demonstrating that echovirus enters susceptible cells by an endocytic pathway and that lactoferrin treatment is able to prevent viral genome delivery into the cytoplasm. It is likely that lactoferrin interaction with echovirus capsid proteins induces alterations that stabilize the conformation of the virion making it resistant to uncoating. Taken together, the results of our study show that the inhibition of echovirus 6 infectivity by lactoferrin is dependent on its interaction not only with cell surface glycosaminoglycan chains but also with viral structural proteins demonstrating that this glycoprotein targets the virus entry process.

Ammonium Chloride↗

PubMed2005

Lactoferrin interaction with retinoid signaling: cell growth and apoptosis in mammary cells.

Lactoferrin (Lf) is a multifunctional iron-binding protein that was first identified in mammary secretions, but is synthesized by most mammalian tissues. The protein has a signal sequence that dictates secretion; it also has a nuclear localization sequence that facilitates entry into the cell nucleus. The mechanism of the latter action is currently unknown, but is thought to occur via a Lf receptor. Lactoferrin content of mammary tissue and secretions varies with developmental state; it is synthesized in mammary tissue at high levels during both pregnancy and involution, and during mammary infections. Using fluorescent (FITC)-labeled holo-bLf, we show that bovine primary epithelial cells and MCF-7 breast cancer cells do not translocate the exogenously added Lf to the nucleus after culture in serum free media (SFM). However, the supplementation of SFM with 1microM all-trans retinoic acid (atRA) caused breast cancer cells to gain the capacity to take up labeled bLf into the cell nucleus. Primary bovine mammary cells (MeBo) exhibited similar capacity in culture. This suggests that in addition to Lf, one or more components modulated by atRA, are necessary for nuclear translocation to occur. Transfection experiments with atRA treated MCF-7 cells containing retinoic acid response element reporter constructs showed that the extracellular application of lactoferrin alters reporter gene expression. Lactoferrin increased a DR5 luciferase response element in a dose-dependent manner only when atRA was applied. Immunocytochemical markers for the cell cycle (Ki67) and apoptotic events (Caspase-3 and PARP-85) showed that lactoferrin alters the atRA-induced phenotype, blocking apoptosis and maintaining cell cycle activity in both MCF-7 and MeBo cells in the presence of 1muM atRA. We propose that nuclear lactoferrin interacts with retinoic acid signaling pathways in cells and alters/blocks the signals so that cells remain in the cell cycle and/or do not enter the apoptotic pathway.

Animals↗

PubMed2004

Lactoferrin enhances peripheral opioid-mediated antinociception via nitric oxide in rats.

Lactoferrin (LF) is a multifunctional protein found in various biological fluids. However, the peripheral action of lactoferrin remains unknown. In this study, peripherally applied bovine lactoferrin showed antinociceptive effect that was reversed by a mu-opioid receptor antagonist, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-NH(2) (CTOP), or by a nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), but not by an inactive enantiomer of L-NAME, N(G)-nitro-D-arginine methyl ester (D-NAME), during phase 1 and phase 2 in the rat formalin test. Peripheral coadministration of a micro-opioid receptor agonist, morphine, with subeffective dose of bovine lactoferrin produced a potentiated antinociceptive effect compared to that of morphine alone during both phases in the formalin test. This potentiated antinociception by morphine with bovine lactoferrin was reversed by CTOP or by L-NAME. These results suggest that bovine lactoferrin exerts an antinociceptive activity via potentiation of the peripheral micro-opioidergic system, and that nitric oxide (NO) is involved in this potentiation.

Analgesics↗

PubMed2005

Lactoferrin-enhanced anoikis: a defense against neonatal necrotizing enterocolitis.

Enteral nutrition with human milk lowers the incidence of necrotizing enterocolitis in preterm human infants. Lactoferrin, the major whey protein in human milk, has many functions related to host defense against bacterial infection. Here, we hypothesize that lactoferrin also helps terminate bacterial invasion of enterocytes via a detachment-induced apoptosis called anoikis. Death of infected epithelia by anoikis prevents local spread of bacterial pathogens because the bacteria are trapped within the cell. Such infected, apoptotic and sloughed epithelia also cannot infect the lower gastrointestinal tract, and the epithelia exit the body in the stool. Currently, anoikis is a phenomenon related to the renewal of enterocytes, and it is not recognized as an anti-bacterial host defense. We suggest that anoikis of infected enterocytes is a process in which lactoferrin plays an important role. In a pilot study in which neonatal rats were pre-treated with intra-gastric recombinant human lactoferrin, we found evidence of epithelia with anoikis in ileal fluid after enteric infection. This finding was rarely seen in infected neonatal rats without pre-treatment with lactoferrin. Quantitative analysis of intestinal lavage specimens and quantitative stereology of apoptotic epithelia in this model will be required to verify the theory. We propose that oral use of recombinant human lactoferrin might have these hypothesized and other anti-bacterial effects in preterm infants, and hence, this protein might prevent necrotizing enterocolitis in preterm infants who cannot take human milk.

Animals↗

PubMed2004

Safety determination for the use of bovine milk-derived lactoferrin as a component of an antimicrobial beef carcass spray.

Bovine milk-derived lactoferrin (BMDL), an iron-binding glycoprotein, is known to be an effective natural antimicrobial. It is used as a spray, applied electrostatically, to raw beef carcasses to detach bacteria adhering to the surface in order to reduce microbial contamination. The use of BMDL as a component (at not more than 2% by weight) of an antimicrobial spray was determined Generally Recognized As Safe (GRAS) (GRN 67) for three proposed uses (i.e., beef carcasses, subprimals, and finished cuts), provided that the ingredient statement of food products that contain milk-derived lactoferrin identifies the source of the protein. The use of BMDL spray on only beef carcasses (not subprimals or finished cuts) at a level not to exceed 0.20 ml of formulation per kg of beef was determined safe without the requirement of labeling of food products so treated. The two key components of the assessment are: (1) a determination that exogenous lactoferrin exposure (resulting from its application to beef carcasses) is in the range of existing background exposures of lactoferrin as a result of lactoferrin found naturally in beef, and (2) a determination that this potentially small incremental increase in lactoferrin is safe (i.e., there is no reasonable expectation that BMDL will become an allergen under the conditions of its intended use).

Animals↗

PubMed2003

New functions of lactoferrin and beta-casein in mammalian milk as cysteine protease inhibitors.

We found new inhibitory function of lactoferrin and beta-casein in milk against cysteine proteases using reverse zymography. The inhibition of cathepsin L by lactoferrin was strongest and the inhibition kinetics were of a non-competitive type. Heat denatured lactoferrin lost the inhibitory activity completely, therefore the tertiary structure is essential to show the inhibition. Native lactoferrin was not degraded by papain during the assay condition. The intramolecular peptide, Y(679)-K(695), of lactoferrin is an active domain and the synthesized peptide inhibited cysteine proteases. The Y(679)-K(695) peptide showed 90% homology with the sequences of a common active site of cystatin family. beta-Casein and the active domain, synthesized L(133)-Q(151), peptide inhibited cysteine proteases. Lactoferrin and beta-casein in milk might play a role in antiseptic and antiinfectious functions due to cysteine protease inhibition of bacteria and viruses.

Amino Acid Sequence↗

PubMed2000

Neutrophil beta(2)-microglobulin and lactoferrin content in renal failure patients.

Multiple dysfunctions of polymorphonuclear leukocytes (PMNLs) contribute significantly to the increased morbidity and mortality among patients with end-stage renal disease. In the present study, we measured the PMNL content of beta(2)-microglobulin (beta(2)m) and lactoferrin in different states of renal insufficiency and after kidney transplantation. PMNLs were lysed ultrasonically and, after centrifugation, both proteins were assayed in the supernatant by enzyme-linked immunosorbent assay technique. Despite marked differences in plasma beta(2)m levels, no significant difference in PMNL content of beta(2)m and lactoferrin could be shown among the groups analyzed. There was also no correlation between plasma beta(2)m level and PMNL beta(2)m content. In control subjects, as well as in renal allograft recipients with a well-functioning graft, PMNL beta(2)m level correlated positively with PMNL lactoferrin level (pooled data, r = 0.55; P < 0.001; n = 55). Both proteins are considered to colocalize in peroxidase-negative PMNL granules. However, no correlation was found in the azotemic and uremic patient groups. Standard immunofluorescence staining of control PMNLs showed a cytoplasmic granular distribution of both granule proteins. However, in PMNLs of uremic patients, lactoferrin shifted to a perinuclear localization. PMNLs obtained from uremic individuals failed to elicit an increase in lactoferrin release after stimulation with the chemotactic peptide f-Met-Leu-Phe compared with PMNLs obtained from healthy volunteers. These data indicate abnormalities in uremic patients of PMNL granule lactoferrin content and release that are reversible after successful renal transplantation.

Adult↗

PubMed2001

Lactoferrin and its biological functions.

Lactoferrin, a component of mammalian milk, is a member of the transferrin family. These glycoproteins transfer Fe(3+) ions. Lactoferrin is a unique polyfunctional protein that influences cell proliferation and differentiation. It can regulate granulopoiesis and DNA synthesis in some cells. Lactoferrin inhibits prostaglandin synthesis in human milk macrophages and activates the nonspecific immune response by stimulating phagocytosis and complement. It can interact with DNA, RNA, proteins, polysaccharides, heparin-like polyanions, etc.; in some of its effects, lactoferrin is found in complexes with ligands. It was recently demonstrated that lactoferrin also possesses ribonuclease activity and is a transcription factor. The list of known biological activities of lactoferrin is constantly increasing. This review analyzes possible mechanisms of its polyfunctionality.

Animals↗

PubMed2003

In vitro growth responses of bifidobacteria and enteropathogens to bovine and human lactoferrin.

A series of in vitro experiments was performed to test the ability of bovine and human lactoferrin to influence the growth of the gram-positive probiotic bacteria, Bifidobacterium bifidum, Bifidobacterium infantis, and Lactobacillus acidophilus, as well as the gram-negative enteric bacteria, E. coli O157:H7 and Salmonella typhimurium. None of the lactoferrin preparations stimulated the growth of the tested strains. However, iron-free apo-lactoferrin (bovine and human) and 66% iron-saturated bovine lactoferrin dramatically slowed the growth of E. coli O157:H7 in single culture experiments, while 98% iron-saturated preparations had no effect. In coculture experiments of B. infantis and E. coli, the iron-limited preparations of lactoferrin also slowed the growth of the latter without inhibiting the bifidobacteria. These results suggest that lactoferrin in iron-limited forms may have the potential to be combined with probiotic bacteria in biotherapeutic products, which could help balance human gut microflora and limit the overgrowth of certain enteric microorganisms.

Animals↗

PubMed2004

Lactoferrin disruption of bacterial type III secretion systems.

Many gram-negative bacteria share a closely related mechanism for secretion of virulence proteins. This complex machine, the type III secretion system, secretes virulence proteins in response to sensing the presence of target mammalian cells. We have found that recombinant human lactoferrin impairs the function of this system in two model organisms: Shigella and Enteropathogenic E. coli (EPEC). In the case of Shigella, there is loss and degradation of two proteins secreted by the type III mechanism, invasion plasmid antigens B and C (IpaB and IpaC); these proteins normally form a complex that causes Shigella to be taken up by host mammalian cells. In the case of EPEC, lactoferrin causes loss and degradation of E. coli secreted proteins A, B and D (EspABD) particularly EspB. These proteins are components of type III machinery and are known to be key elements of EPEC pathogenesis. Studies using purified EspB demonstrated that lactoferrin has a direct proteolytic effect on EspB that can be prevented by serine protease inhibitors. A synthetic peptide of the N-terminal 33 amino acids of lactoferrin caused loss of cell associated EspB but, unlike the whole lactoferrin molecule, did not caused degradation of EspB. Thus, in both model systems, brief exposure to lactoferrin causes loss and degradation of type III secretion system virulence proteins.

Bacterial Proteins↗

PubMed2004

Methylation and expression of the lactoferrin gene in human tissues and cancer cells.

The lactoferrin gene promoter contains GC-rich regions that harbor consensus sequences for a variety of transcription factors. Previous work in our laboratory has demonstrated a link between methylation at the CpG sites of the mouse lactoferrin gene promoter and the level of its expression. The current work investigates the methylation profile in three regions of the human lactoferrin gene by bisulfite genomic sequencing. In addition, the methylation profiles of normal leukocyte DNA, and leukemia cell line and patient DNA were compared. The three regions are located at the -504/-190, which includes the estrogen response element, the -282/+271 which contains the lactoferrin promoter and the +1087/+1476, a region within the first intron that has the alternative delta lactoferrin promoter. Differential methylations were found within all the regions. Increased methylation at the CpG sites and the presence of non-CpG methylation of the lactoferrin promoters were found in the cancer samples.

Animals↗

PubMed2002

Experimental immune-mediated pancreatitis in neonatally thymectomized mice immunized with carbonic anhydrase II and lactoferrin.

We previously reported that autoantibodies against carbonic anhydrase II and lactoferrin are frequently identified in patients with autoimmune-related pancreatitis. To clarify the role of carbonic anhydrase II and lactoferrin, we created animal models of autoimmune pancreatitis by immunizing neonatally thymectomized mice with carbonic anhydrase II and lactoferrin and also by transferring immunized spleen cells to nude mice. Neonatally thymectomized BALB/c mice were immunized with carbonic anhydrase II or lactoferrin followed by three booster injections (n = 10 in each group). We transferred whole, CD4+, or CD8+ spleen cells prepared from immunized neonatally thymectomized mice to nude mice (n = 5 in each group). Gene expression of IFN-gamma and IL-4 was investigated using semiquantitative reverse transcription-polymerase chain reaction. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling staining was used to examine apoptosis. In immunized neonatally thymectomized mice, the prevalence of inflammation was significantly higher in the pancreas. Inflammation was present in all mice receiving whole or CD4+ cells. There was no change in any of the mice receiving CD8+ cells or nonimmunized spleen cells. Carbonic anhydrase II or lactoferrin-immunized mice had apoptotic duct cells or acinar cells, respectively. Expression of the IFN-gamma gene was up-regulated in each group. Similar findings were observed in the salivary glands and liver. An immunologic mechanism against carbonic anhydrase II or lactoferrin is involved in the pathogenesis of these pancreatitis models, in which the effector cells are Th1-type CD4+ T cells.

Adoptive Transfer↗

PubMed2006

Mother's iron status, breastmilk iron and lactoferrin--are they related?

OBJECTIVE: Exclusive breastfeeding is recommended till 6 months age. Factors regulating the breastmilk iron and lactoferrin levels are incompletely known. Considering high prevalence of nutritional anemia in lactating mothers, we studied the iron status of lactating mothers, their breastmilk iron and lactoferrin levels to determine any relationship between them. DESIGN: Prospective study with 6 months follow-up. SETTING: Tertiary care referral hospital. SUBJECTS: Hundred nonanemic and 100 anemic mothers with their babies recruited at birth. Fifty-two nonanemic and 50 anemic mothers and their babies completed the 6-month follow-up. INTERVENTIONS: Hemoglobin (Hb), total iron binding capacity (TIBC), percent transferrin saturation (%TS), serum iron (SI) and serum ferritin measured on day 1 and 6 months postpartum. Breastmilk iron and lactoferrin measured on day 1, 14 weeks and 6 months after delivery. RESULTS: Breastmilk iron decreased progressively from day 1 to 14 weeks and at 6 months in both groups, but no significant difference was noted between nonanemic and anemic mothers (P>0.05). Significant decline in breastmilk lactoferrin concentration from day 1 to 14 weeks in nonanemic and anemic mothers (P<0.001) noted. Hemoglobin, TIBC, %TS, SI and serum ferritin of both groups had no correlation with breastmilk iron and lactoferrin concentration on day 1, 14 weeks and 6 months after delivery. CONCLUSIONS: Breastmilk iron and lactoferrin concentration had no relationship with the mother's Hb and iron status.

Adult↗

PubMed1991

Expression of cloned human lactoferrin in baby-hamster kidney cells.

Human lactoferrin was expressed from a cloned cDNA introduced into mammalian cells in tissue culture. Total RNA was extracted from human bone marrow, and lactoferrin cDNA was synthesized by primer-specific polymerase chain reaction after oligo(dT)-primed first-strand synthesis. The cDNA was sequenced to confirm its identity with previously published human lactoferrin sequences and cloned into the eukaryotic expression vector pNUT. Recombinant vector DNA containing the human lactoferrin sequence was introduced into baby-hamster kidney (BHK) cells in culture, and stable transfectants were produced by dominant marker selection. Human lactoferrin was expressed from the metallothionein promoter of pNUT by Zn2+ induction. The protein was secreted into the tissue-culture medium and was subsequently purified to homogeneity in a single step. Initial characterization suggests that the protein expressed by BHK cells is identical with native human lactoferrin.

Amino Acid Sequence↗

PubMed1979

Lactoferrin turnover in man.

1. The turnover of 125I-labelled lactoferrin was measured in ten adults. Simultaneous organ radioactivity counting was performed. 2. Ferrokinetic studies were performed in three adults after the intravenous injection of [59Fe]lactoferrin. 3. Lactoferrin was rapidly eliminated from the plasma with a mean fractional catabolic rate of 5.7/day. Apolactoferrin (one subject) was eliminated at a slower rate (fractional catabolic rate 1.22/day). 4. Of the administered 125I label 99% was recovered in the urine, as free iodine, within the first 24 h. In the 59Fe studies no appreciable activity was found in the urine. 5. Organ radioactivity counting showed that lactoferrin was rapidly taken up by the liver and spleen. In the 125I studies the rapid excretion of free 125I suggested catabolism at these sites. In the 59Fe studies, the radioactivity persisted in the liver and spleen for several weeks and was slowly transferred to the bone marrow before appearing in circulating erythrocytes. 6. From the values of fractional catabolic rate, plasma lactoferrin, neutrophil lactoferrin and plasma volume, a 'derived neutrophil turnover' was calculated for each subject. The mean value was 8 x 10(8) neutrophils/day. This is about 1% the value obtained from the actual measurement of labelled cells. It is postulated that this 'derived value' represents only that portion of neutrophil turnover accounted for by intravascular senescence.

Adult↗

PubMed2004

Fecal lactoferrin for diagnosis of symptomatic patients with ileal pouch-anal anastomosis.

BACKGROUND & AIMS: Increased stool frequency, urgency, and abdominal pain in patients with ileal pouch-anal anastomosis (IPAA) may be due to inflammatory conditions, including pouchitis, cuffitis, or Crohn's disease or noninflammatory conditions such as irritable pouch syndrome. Distinction among these entities requires pouch endoscopy and biopsy. Noninvasive means of diagnosis are preferable. METHODS: Sixty consecutive subjects with IPAA for inflammatory bowel disease had measurements of fecal lactoferrin and alpha1-antitrypsin and underwent pouch endoscopy with biopsy, with calculation of the pouchitis disease activity index in a prospective cross-sectional study. RESULTS: Symptomatic patients with an inflammatory condition had significantly higher fecal lactoferrin concentrations (median, 176.0 microg/mL, interquartile range [IQR] 79.0-450.8) compared with those with a noninflammatory condition (median, 4.8 microg/mL; IQR, 1.2-11.0) or those who were asymptomatic (median, 7.8 microg/mL; IQR, 1.4-12.9), P < 0.001. At a cutoff level of 7 microg/mL, fecal lactoferrin could distinguish patients with irritable pouch syndrome from those with pouchitis, cuffitis, or Crohn's disease with a sensitivity of 100% and specificity of 85%. Fecal alpha1-antitrypsin was not able to distinguish symptomatic patients with and without an inflammatory condition. CONCLUSIONS: Fecal lactoferrin can serve as a sensitive and noninvasive initial screening test in an algorithm for evaluation of symptomatic patients with IPAA. If fecal lactoferrin levels are low (<7 microg/mL), IPS can be diagnosed. If fecal lactoferrin levels are high, pouch endoscopy with biopsy is warranted to distinguish among different causes of inflammation. Longitudinal studies are needed to define better the role of this test in the management of patients with IPAA.

Adult↗

PubMed2004

Variable expression of human lactoferrin gene in mice milk driven by its 90 KB upstream flanking sequences.

One major drawback in research of animal mammary gland bioreactors is the low production rate of high-expressing transgenic animals due to position effects. To obtain high and stable expression of foreign gene, yeast and bacterial artificial chromosome have been used as transgene vector in recent research. Human lactoferrin is a bioactive, versatile protein, and has large potential in nutritional and therapeutic applications. Therefore, production of recombinant lactoferrin using animal bioreactors was studied widely to satisfy its large requirement. We reported here a transgenic mice model with high-level expression of recombinant human lactoferrin in mammary gland. Transgene construct used here was a human bacterial artificial chromosome containing intact lactoferrin-encoding transcript unit, approximately 90 kb 5'-flanking sequences and 27.2 kb 3'-flanking sequences. We obtained totally 10 transgenic mice whereas two of them lacked of part of upstream sequences of the gene. Milk of eight transgenic mice line was detected by Western blot and radioimmunoassay and seven lines expressed recombinant human lactoferrin at high but variable level (0.29, 0.53, 0.90, 1.23, 2.76, 3.58, and 8.02 mg/mL, respectively). The variability of expression indicates that even the 90 kb 5' flanking sequence of the transgene can't overcome position effects completely. Moreover, we also determined sequences of 9.3 kb regulatory region and 10.6 kb encoding region of the gene and thus supplemented all unknown sequences. Our results suggested that transgene vector used here has potential to be used in large farm animals for production of recombinant human lactoferrin in industrial scale.

Animals↗

PubMed2004

Lactoferrin enhances Fas expression and apoptosis in the colon mucosa of azoxymethane-treated rats.

Bovine lactoferrin, a multifunctional glycoprotein, has been shown to strongly inhibit development of azoxymethane (AOM)-induced rat colon tumors. Little, however, is known about the inhibitory mechanisms. We have demonstrated recently that lactoferrin enhances the expression of a member of the tumor necrosis factor receptor family, Fas, in the colon mucosa during both early and late stages of carcinogenesis. Thus, Fas could be involved in bovine lactoferrin-mediated inhibition of tumor development. To investigate this possibility, we studied the influence of bovine lactoferrin on Fas-mediated apoptosis with regard to expression of Fas, activation of caspase-8 and caspase-3, and DNA fragmentation in the colon mucosa of AOM-treated rats. Western blot analysis demonstrated a >2.5-fold increase in Fas protein expression, as well as elevation of the active forms of both caspase-8 and caspase-3. Immunohistochemical analysis revealed Fas-positive cells and apoptotic cells preferentially within the proximal colon region, clearly at the site of bovine lactoferrin-mediated tumor inhibition. These results suggest that apoptosis caused by elevated expression of Fas is involved in chemoprevention by lactoferrin of colon carcinogenesis.

Animals↗