Lactoferrin: structure, function and applications

doi:10.1016/j.ijantimicag.2008.07.020

International Journal of Antimicrobial Agents

Volume 33, Issue 4, April 2009, Pages 301.e1-301.e8

https://doi.org/10.1016/j.ijantimicag.2008.07.020 Get rights and content

Abstract

Lactoferrin (LF) is an 80 kDa iron-binding glycoprotein of the transferrin family that is expressed in most biological fluids and is a major component of the mammalian innate immune system. Its protective effects range from direct antimicrobial activities against a large panel of microorganisms, including bacteria, viruses, fungi and parasites, to anti-inflammatory and anticancer activities. These extensive activities are made possible by mechanisms of action utilising not only the capacity of LF to bind iron but also interactions of LF with molecular and cellular components of both host and pathogens. This review summarises the putative antimicrobial mechanisms, clinical applications and heterologous expression models for LF.

Introduction

Lactoferrin (LF) is a non-haem iron-binding protein that is part of the transferrin protein family, along with serum transferrin, ovotransferrin, melanotransferrin and the inhibitor of carbonic anhydrase [1], whose function is to transport iron in blood serum. LF is produced by mucosal epithelial cells in various mammalian species, including humans, cows, goats, horses, dogs and several rodents. Recent studies have shown that LF is also produced by fish, as it has been identified in rainbow trout eggs using molecular biology techniques [2]. This glycoprotein is found in mucosal secretions, including tears, saliva, vaginal fluids, semen [3], nasal and bronchial secretions, bile, gastrointestinal fluids, urine [4] and most highly in milk and colostrum (7 g/L) [5], making it the second most abundant protein in milk [6], after caseins. It can also be found in bodily fluids such as blood plasma and amniotic fluid. LF is also found in considerable amounts in secondary neutrophil granules (15 μg/10⁶ neutrophils) [7], where it plays a significant physiological role. LF possesses a greater iron-binding affinity and is the only transferrin with the ability to retain this metal over a wide pH range [8], including extremely acidic pH. It also exhibits a greater resistance to proteolysis. In addition to these differences, LF’s net positive charge and its distribution in various tissues make it a multifunctional protein. It is involved in several physiological functions, including: regulation of iron absorption in the bowel; immune response; antioxidant, anticarcinogenic and anti-inflammatory properties; and protection against microbial infection, which is the most widely studied function to date. The antimicrobial activity of LF is mostly due to two mechanisms. The first is iron sequestration in sites of infection, which deprives the microorganism of this nutrient, thus creating a bacteriostatic effect. The other mechanism is the direct interaction of the LF molecule with the infectious agent. The positive amino acids in LF can interact with anionic molecules on some bacterial, viral, fungal and parasite surfaces, causing cell lysis.

Considering the physiological capabilities of LF in host defence, in addition to current pharmaceutical and nutritional needs, LF is considered to be a nutraceutical and for several decades investigators have searched for the most convenient way to produce it. Today, we can obtain it as native LF isolated mostly from the milk and colostrum of several mammals, or as recombinant LF (rLF) generated from bacterial, fungal and viral expression systems. The expression of this protein has also been attained in higher organisms such as plants and mammals.

Section snippets

Structure and properties

LF (Fig. 1) is an 80 kDa glycosylated protein of ca. 700 amino acids with high homology among species. It is a simple polypeptide chain folded into two symmetrical lobes (N and C lobes), which are highly homologous with one another (33–41% homology). These two lobes are connected by a hinge region containing parts of an α-helix between amino acids 333 and 343 in human LF (hLF) [1], which provides additional flexibility to the molecule [3]. The polypeptide chain includes amino acids 1–332 for the

Biological functions of lactoferrin

Several functions have been attributed to LF. It is considered a key component in the host’s first line of defence, as it has the ability to respond to a variety of physiological and environmental changes [6]. The structural characteristics of LF provide functionality in addition to the Fe³⁺ homeostasis function common to all transferrins: strong antimicrobial activity against a broad spectrum of bacteria, fungi, yeasts, viruses [5] and parasites [11]; anti-inflammatory and anticarcinogenic

Bioactive peptides derived from lactoferrin

Since it was first isolated in 1960 [71], LF has been widely studied for its antimicrobial characteristics. One of the main mechanisms used by LF is Fe³⁺ sequestration. However, it is known that LF may also interact directly with the pathogen [10]. Enzymatic treatment of bLF with pepsin produced a low-molecular-weight peptide with antibacterial properties against a large number of Gram-positive and Gram-negative bacteria, including Escherichia coli, Salmonella enteritidis, K. pneumoniae,

Lactoferrin gene regulation

LF has been identified in several tissues both in humans and animals and it has extensive homology among species. Its mRNA levels vary by tissue, suggesting tissue- or cell-specific regulation [75], [76], [77], [78].

To date, the LF gene has been found at the chromosome level in a set of different species (human chromosome 3 [79] and mouse chromosome 9 [80]) and its size ranges from 23 kb to 35 kb. The LF gene is organised in 17 exons, 15 of which are identical in cows, pigs and mice [81]. In

Clinical applications of lactoferrin

On account of LF’s many functions, it has been tested for clinical use in disease prevention, treatment and diagnosis.

One of the first applications of LF was in infant formula. Several studies showed that infants fed with infant formulas had less intestinal iron absorption than breastfed infants [13], [14]. Most of the LF is absorbed intact by the infant’s bowel, and thus LF is distributed by the bloodstream. LF also promotes the proliferation of lactic acid bacteria in the bowel such as

Production of native and recombinant lactoferrin

Because of the functional characteristics of LF, attempts have been made to produce or purify this protein for use as a food additive or therapeutic. Protein purification strategies are based on the properties of the molecule and depend on three types of chromatography. Since LF has a net positive charge [3], it is efficiently absorbed on cation exchange resins and is eluted with saline solutions [89] at >95% purity [90]. LF binds Fe³⁺ so it can be purified by metal ion affinity chromatography

Concluding remarks

A wide spectrum of functions have been described for LF. The beneficial effect of LF in the treatment of various infectious diseases caused by bacteria, fungi, protozoa and viruses in animals and humans is described above. Despite extensive literature available on LF, the molecular interactions of this protein with regulatory elements and other proteins for antimicrobial function require further investigation. The great utility of this functional protein has motivated scientists to overexpress

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Lactoferrin as a therapeutic agent for attenuating hepatic stellate cell activation in thioacetamide-induced liver fibrosis
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Liver fibrosis is a chronic liver disease caused by prolonged liver injuries. Excessive accumulation of extracellular matrix replaces the damaged hepatocytes, leading to fibrous scar formation and fibrosis induction. Lactoferrin (LF) is a glycoprotein with a conserved, monomeric signal polypeptide chain, exhibiting diverse physiological functions, including antioxidant, anti-inflammatory, antibacterial, antifungal, antiviral, and antitumoral activities. Previous study has shown LF’s protective role against chemically-induced liver fibrosis in rats. However, the mechanisms of LF in liver fibrosis are still unclear. In this study, we investigated LF’s mechanisms in thioacetamide (TAA)-induced liver fibrosis in rats and TGF-β1-treated HSC-T6 cells. Using ultrasonic imaging, H&E, Masson's, and Sirius Red staining, we demonstrated LF’s ability to improve liver tissue damage and fibrosis induced by TAA. LF reduced the levels of ALT, AST, and hydroxyproline in TAA-treated liver tissues, while increasing catalase levels. Additionally, LF treatment decreased mRNA expression of inflammatory factors such as Il-1β and Icam-1, as well as fibrogenic factors including α-Sma, Collagen I, and Ctgf in TAA-treated liver tissues. Furthermore, LF reduced TAA-induced ROS production and cell death in FL83B cells, and decreased α-SMA, Collagen I, and p-Smad2/3 productions in TGF-β1-treated HSC-T6 cells. Our study highlights LF's ability to ameliorate TAA-induced hepatocyte damage, oxidative stress, and liver fibrosis in rats, potentially through its inhibitory effect on HSC activation. These findings suggest LF's potential as a therapeutic agent for protecting against liver injuries and fibrosis.
Analyzing the interaction of Helicobacter pylori GAPDH with host molecules and hemin: Inhibition of hemin binding
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Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a moonlighting enzyme. Apart from its primary role in the glycolytic pathway, in many bacterial species it is found in the extracellular milieu and also on the bacterial surface. Positioning on the bacterial surface allows the GAPDH molecule to interact with many host molecules such as plasminogen, fibrinogen, fibronectin, laminin and mucin etc. This facilitates the bacterial colonization of the host. Helicobacter pylori is a major human pathogen that causes a number of gastrointestinal infections and is the main cause of gastric cancer. The binding analysis of H. pylori GAPDH (HpGAPDH) with host molecules has not been carried out. Hence, we studied the interaction of HpGAPDH with holo-transferrin, lactoferrin, haemoglobin, fibrinogen, fibronectin, catalase, plasminogen and mucin using biolayer interferometry. Highest and lowest binding affinity was observed with lactoferrin (4.83 ± 0.70 × 10⁻⁹ M) and holo-transferrin (4.27 ± 2.39 × 10⁻⁵ M). Previous studies established GAPDH as a heme chaperone involved in intracellular heme trafficking and delivery to downstream target proteins. Therefore, to get insights into heme binding, the interaction between HpGAPDH and hemin was analyzed. Hemin binds to HpGAPDH with an affinity of 2.10 μM while the hemin bound HpGAPDH does not exhibit activity. This suggests that hemin most likely binds at the active site of HpGAPDH, prohibiting substrate binding. Blind docking of hemin with HpGAPDH also supports positioning of hemin at the active site. Metal ions were found to inhibit the activity of HpGAPDH, suggesting that it also possibly occupies the substrate binding site. Furthermore, with metal-bound HpGAPDH, hemin binding was not observed, suggesting metal ions act as an inhibitor of hemin binding. Since GAPDH has been identified as a heme chaperone, it will be interesting to analyse the biological consequences of inhibition of heme binding to GAPDH by metal ions.
Highly specific colloidal ɣ-Fe<inf>2</inf>O<inf>3</inf>-DNA hybrids: From bioinspired recognition to large-scale lactoferrin purification
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The industry transfer of laboratory-use magnetic separation is still hampered by the lack of suitable nanoparticles, both in terms of their features and large-scale availability. Surface Active Maghemite Nanoparticles (SAMNs) characterized by a unique surface chemistry, low environmental impact, scalable synthesis and functionalization were used to develop a bio-inspired lactoferrin (LF) recognition system. Based on the LF affinity for DNA, a self-assembly process was optimized for obtaining a SAMN@DNA hybrid displaying chemical and colloidal stability and LF specificity. SAMN@DNA was successfully tested for the affinity purification of LF from crude bovine whey. Advantages, such as high selectivity and loading capacity, nanoparticle re-usability, outstanding purity (96 ± 1%), preservation of protein conformation and short operational time, were highlighted. Finally, scalability was demonstrated by an automatic system performing continuous purification of LF from 100 liters day⁻¹ of whey. This study responds to essential prerequisites, such as efficiency, re-usability and industrialization feasibility.
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This study demonstrated the purification of bovine lactoferrin (BLF), caprine lactoferrin (CLF) and ovine lactoferrin (OLF) by ion-exchange chromatography and gel filtration chromatography. The purified lactoferrin (LF) were identified by mass spectrometry and its purity was analyzed by RP-HPLC. LFs with different iron saturations were established, and it was found that iron saturation of Holo-CLF (62.01%) and Holo-OLF (63.74%) were lower than Holo-BLF (83.93%). The effect of iron saturation on the physicochemical properties of LFs were evaluated by circular dichroism, Fourier transform infrared spectroscopy and differential scanning calorimetry. The results showed that both species and iron saturation did not affect the secondary structure of LFs, however, they did influence tertiary structure of LFs. The conformation of Holo-LFs was more compact than that of Apo-LFs. Furthermore, Native-OLF showed the tightest conformation, followed by Native-BLF and Native-CLF. In addition, the increase of iron saturation enhanced the thermal stability of LFs in all three species. Among three species, Apo-OLF was the most thermally stable in among three species due to its more compact structure, while Holo-BLF was the most thermally stable among three species due to its highest iron saturation. Although Native-CLF had a relatively lower iron saturation compared to BLF and OLF, its thermal stability was relatively higher as the main denaturation temperature peak of CLF was located at 85.65 °C. These findings would contribute to further understanding of the information of LFs at different iron saturation levels, which is crucial for the production and application of LFs in the future.
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ReviewLactoferrin: structure, function and applications

Abstract

Introduction

Section snippets

Structure and properties

Biological functions of lactoferrin

Bioactive peptides derived from lactoferrin

Lactoferrin gene regulation

Clinical applications of lactoferrin

Production of native and recombinant lactoferrin

Concluding remarks

Antiviral Res

Biochim Biophys Acta

J Mol Biol

J Pediatr

Antiviral Res

Blood

Clin Chim Acta

Exp Cell Res

Protein Expr Purif

Protein Expr Purif

Bovine mammary lactoferrin: implications from messenger ribonucleic acid (mRNA) sequence and regulation contrary to other milk proteins

J Dairy Sci

Detección de lysozima and lactoferrin por western blot en ovas de Trucha arcoíris (Oncorhynchus mykiss)

Mundo Pecuario

Lactoferrin: a multifunctional protein

Adv Mol Med

Antimicrobial mechanisms and potential clinical application of lactoferrin [in Spanish]

Rev Latinoam Microbiol

Antiinflammatory activities of lactoferrin

J Am Coll Nutr

Lactoferrin content of peripheral blood cells

Br J Haematol

Actividades antibacterianas de la lactoferrina

Enf Inf Microbiol

Bovine lactoferrin: benefits and mechanism of action against infections

Biochem Cell Biol

Multiple enzymatic activities of human milk lactoferrin

Eur J Biochem

Iron absorption from infant milk formula and the optimal level of iron supplementation

Acta Paediatr Scand

Lactoferrin, lactoferrin receptors and iron metabolism

Eur J Clin Nutr

Iron status in mice carrying a targeted disruption of lactoferrin

Mol Cell Biol

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

Proc Natl Acad Sci USA

Potential antimicrobial effects of human lactoferrin against oral infection with Listeria monocytogenes in mice

J Med Microbiol

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

J Appl Microbiol

Both lactoferrin and iron influence aggregation and biofilm formation in Streptococcus mutans

Biometals

Effect of ovotransferrin and lactoferrins on Chlamydophila psittaci adhesion and invasion in HD11 chicken macrophages

Vet Res

Lactoferrin impairs type III secretory system function in enteropathogenic Escherichia coli

Infect Immun

Human milk fractions inhibit the adherence of diffusely adherent Escherichia coli (DAEC) and enteroaggregative E. coli (EAEC) to HeLa cells

FEMS Microbiol Lett

Recombinant human lactoferrin is effective in the treatment of Helicobacter felis-infected mice

J Pharm Pharmacol

Inhibition of Helicobacter pylori infection by bovine milk glycoconjugates in a BAlb/cA mouse model

J Med Microbiol

Metal complexes of lactoferrin and their effect on the intracellular multiplication of Legionella pneumophila

Biometals

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

J Infect Dis

In vitro adhesion and invasion inhibition of Shigella dysentariae, Shigella flexneri and Shigella sonnei clinical strains by human milk proteins

BMC Microbiol

Correction of the iron overload defect in β-2-microglobulin knockout mice by lactoferrin abolishes their susceptibility to tuberculosis

J Exp Med

El hierro and la virulencia bacteriana

Enf Inf Microbiol

Damage of the membrane of enteric Gram-negative bacteria by lactoferrin and transferrin

Infect Immun

Quantitation of metal cations bound to membranes and extracted lipopolysaccharide of Escherichia coli

Biochemistry

Killing of Gram-negative bacteria by lactoferrin and lysozyme

J Clin Invest

Elucidation of the antistaphylococcal action of lactoferrin and lysozyme

Review
Lactoferrin: structure, function and applications