Bovine Lactoferrin Stimulates the Phagocytic Activity of Human Neutrophils: Identification of Its Active Domain

doi:10.1006/cimm.1997.1246

Cellular Immunology

Volume 187, Issue 1, 10 July 1998, Pages 34-37

https://doi.org/10.1006/cimm.1997.1246 Get rights and content

Abstract

Bovine LF (bLF) at concentrations in the range of 50–250 μg/ml enhanced the phagocytic activity of human neutrophils as determined by measuring the incorporation of FITC-labeled latex beads by flow cytometry. The stimulatory effect of bLF was not abrogated by hydrolysis with pepsin. Bovine lactoferricin (bLFcin), which is a bactericidal fragment purified from a pepsin hydrolysate of bLF (bLFH), also enhanced the phagocytic activity, whereas, in contrast, the fraction of bLFH depleted of bLFcin showed no stimulatory effect. The phagocytosis-enhancing activity of bLF still remained after washing the neutrophils, following exposure to bLF. Also, bLF pretreatment of the latex beads stimulated their uptake. These results demonstrate that bLF is effective in promoting the phagocytic activity of human neutrophils. This activity appears to be due to its bLFcin domain and may involve dual mechanisms of direct binding to neutrophils and opsonin-like activity.

References (29)

W. Bellamy et al.
Biochim. Biophys. Acta
(1992)
J.A. Lash et al.
Blood
(1983)
M. Tomita et al.
J. Dairy Sci.
(1991)
W. Pruzanski et al.
Exp. Cell Res.
(1978)
H. Wu et al.
Blood
(1995)
A.S. Naidu et al.
J. Dairy Sci.
(1991)
M. Sakai et al.
Comp. Biochem. Physiol. Ser. B
(1995)
P.L. Masson et al.
Clin. Chim. Acta
(1996)
R.A. Finkelstein et al.
Rev. Infect. Dis.
(1983)
R.R. Arnold et al.
Science
(1977)

C.A. Bortner et al.

Infect. Immun.

(1986)

R.T. Ellison et al.

Infect. Immun.

(1988)

J.H. Brock

Arch. Dis. Child.

(1985)

B. Lönnerdal et al.

Annu. Rev. Nutr.

(1995)

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Previously we have shown that lactoferrin (LTF), a protein of secondary neutrophilic granules, can be efficiently modified by hypohalous acids (HOCl and HOBr), which are produced at high concentrations during inflammation and oxidative/halogenative stress by myeloperoxidase, an enzyme of azurophilic neutrophilic granules. Here we compared the effects of recombinant human lactoferrin (rhLTF) and its halogenated derivatives (rhLTF-Cl and rhLTF-Br) on functional responses of neutrophils. Our results demonstrated that after halogenative modification, rhLTF lost its ability to induce mobilization of intracellular calcium, actin cytoskeleton reorganization, and morphological changes in human neutrophils. Moreover, both forms of the halogenated rhLTF prevented binding of N-acetylglucosamine-specific plant lectin Triticum vulgaris agglutinin (WGA) to neutrophils and, in contrast to native rhLTF, inhibited respiratory burst of neutrophils induced by N-formyl-L-methionyl-L-leucyl-L-phenylalanine and by two plant lectins (WGA and PHA-L). However, we observed no differences between the effects of rhLTF, rhLTF-Cl, and rhLTF-Br on respiratory burst of neutrophils induced by phorbol 12-myristate 13-acetate (PMA), digitonin, and number of plant lectins with different glycan-binding specificity. Furthermore, all rhLTF forms interfered with PMA- and ionomycin-induced formation of neutrophil extracellular traps. Thus, halogenative modification of LTF is one of the mechanisms involved in modulating a variety of signaling pathways in neutrophils to control their pro-inflammatory activity.
Effects of lactoferrin on infectious diseases in Japanese summer: A randomized, double-blinded, placebo-controlled trial
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To investigate the effects of lactoferrin (LF) on infectious diseases in Japanese summer.
An intake of placebo, 200 mg, or 600 mg of LF were administered to healthy adults in Kyushu University of Health and Welfare for 12 weeks in a randomized, double-blinded, placebo-controlled parallel-group comparative trial. The primary endpoints were the prevalence and duration of infectious diseases and changes in immune parameters.
Three hundred and ten subjects were randomized (placebo, n = 104; 200 mg, n = 103; 600 mg, n = 103). Twenty subjects were lost to the follow-up, leaving 290 for a full analysis set (n = 99; n = 95; n = 96). The duration (day) of total infectious diseases was shorter in the 200 mg group (2.0, p = 0.045) and 600 mg group (2.0, p = 0.010) than in the placebo group (3.0). The duration of summer colds was shorter in the 600 mg group (2.0, p = 0.036) than in the placebo group (3.0). No significant differences were observed in the prevalence of infectious diseases or changes in immune parameters. In exploratory investigations, changes in the neutrophil phagocytic capacity, cortisol concentrations, and T score of “Vigor/Activity” in the Profile of Mood States 2 were greater in the 600 mg group than in the placebo group, when analysis was done on the lower half groups at the baseline. Adverse events were similar in each group and none had a causal relationship with the intake of the test foods.
In summer, the intake of LF attenuates infectious diseases, including summer colds.
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Citation Excerpt :
Glycomacropeptide (GMP), a fragment of 64-amino acid residues derived from bovine κ-casein (residues 106–169) can enhance the phagocytic activity and proliferation of human macrophage-like cells (Li and Mine, 2004) and induce cytokine expression in monocytes through NF-κB and MAPK signaling (Requena et al., 2009). Lactoferricin B, a pepsin hydrolysate of bovine lactoferrin (LF, residues 17-41), could enhance the phagocytic ability of human neutrophils through direct binding to neutrophils and opsonin-like effect (Miyauchi et al., 1998). Administration of the casein derived tripeptide VPP inhibited macrophage accumulation and activation in fat tissues in the diet-induced obese mice (Sawada et al., 2015).
Modulation of immune responses by immunoregulatory agents, such as the natural or synthetic immunomodulatory peptides, has been suggested as a potential strategy to modulate immune system against infection and other immune-related diseases. These compositionally simple peptides have attracted much attention for many drug developers, due to their high activity, low toxicity and clear target specificity. Host defence peptides and milk-derived peptides are two kinds of natural immunomodulatory peptides which have been widely studied in mammalians. They could participate at the interface of innate and adaptive immunity by regulating immune effector cells. This review summarizes the recent advances in host defence peptides and milk-derived peptides as well as their general characteristics, immunomodulatory functions and possible applications.
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Citation Excerpt :
However, vaccination in addition to infection with E. coli changed the balance of cytokines away from increasing inflammation (Belkaid and Hand, 2014). The phagocytic heterophil levels detected in the NBT test were elevated in the infected group at 7 dpi, which may be due to fragments and lactoferrin from the bacteria encouraging the phagocytic process (Hashimoto et al., 1998). In addition, the reduced phagocytic activity of the infected group may be related to stress of infection (Ali et al., 2013; Eladl et al., 2019).
Viral haemorrhagic disease (VHD) and colibacillosis are common diseases in rabbits that cause economic losses worldwide. The effect of colibacillosis on the immune response of vaccinated rabbits against rabbit haemorrhagic disease virus (RHDV) was studied. Four groups (G1-G4) were included. G1 was the negative control group; G2 was the RHDV vaccine group; G3 was the E. coli-infected group; and G4 was the E. coli-infected + RHDV vaccine group. The E. coli infection and RHDV vaccination were simultaneously performed, with another previous infection, 3 days before vaccination. At 28 days post-vaccination (PV), the rabbits (G2-G4) were challenged intramuscularly with 0.5 ml of RHDV at a dose of 10³ 50% median lethal dose (LD₅₀)/rabbit. The rabbits were observed for clinical signs, body weight gain and mortality rates. Tissue, blood, serum, and faecal samples and rectal swabs were collected at 3, 5, 7, 14, 21 and 28 days PV. Significant clinical signs and mortality and a decrease in BW were observed in the infected + RHDV vaccine group. On the 3^rd day post-infection (PI), compared with all the other groups, the vaccinated group (G2) had significantly upregulated hepatic tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels; however, the infected + RHDV vaccine group had significantly higher intestinal levels of TNF-α and IL-6 than the other groups. Furthermore, E. coli infection in vaccinated rabbits led to immunosuppression, as shown by significant decreases (P < 0.05) in heterophil phagocytic activity, the CD4+/CD8+ ratio, and HI antibody responses to RHDV and a significant increase in the heterophil to lymphocyte (H/L) ratio. In conclusion, colibacillosis leads to immunosuppression involving a shift in the equilibrium of cytokines and reduced weight gain and mortality in vaccinated rabbits and could be a contributing factor in RHDV vaccination failure in rabbit farming.
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Lactoferrin is a non-heme iron-binding glycoprotein with multiple health-beneficial functions including antimicrobial, antioxidant, anticarcinogenic, and immunomodulatory effects. There is emerging evidence that neutrophils may serve as targets of lactoferrin in vivo, and here we show how recombinant human lactoferrin (rhLf) can contribute to this regulation. Indeed, our results demonstrate that rhLf binds efficiently to human neutrophils and induces a variety of early cellular responses such as mobilization of intracellular Ca²⁺, remodeling of actin cytoskeleton, and degranulation (release of lysozyme and myeloperoxidase). In addition, rhLf facilitates lectin-induced H₂O₂ production and stabilization of lectin-induced cellular aggregates. The role of calcium signaling seems to be essential for rhLf-induced activation of neutrophils, as Ca²⁺-chelators inhibit degranulation response while lectin-induced H₂O₂ production correlates significantly with cytoplasmic Ca²⁺ elevation. Taken together, our findings justify that rhLf can activate neutrophil functions in a calcium-dependent manner and hence, can potentiate innate immune responses.
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The advent of functional foods has been facilitated by increasing scientific knowledge about the metabolic and genomic effects of diet and specific dietary components on human health. During the last decade, major advances and developments have been achieved in the science, technology, and commercial applications of milk-derived bioactive components. Milk peptides are regarded as important components for health-promoting foods under nutraceutical applications due to their physiological and physicochemical versatility. As yet, no clinical trials have been performed with milk-derived peptides, but their activities were confirmed in vitro and in animal studies. To establish prophylactic and therapeutic value of bioactive peptides, new strategies/research models having better correlation with clinical trials along with studies on their mechanism of action have been discussed in this chapter.

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Regular ArticleBovine Lactoferrin Stimulates the Phagocytic Activity of Human Neutrophils: Identification of Its Active Domain

Abstract

Biochim. Biophys. Acta

Blood

J. Dairy Sci.

Exp. Cell Res.

Blood

J. Dairy Sci.

Comp. Biochem. Physiol. Ser. B

Clin. Chim. Acta

Rev. Infect. Dis.

Science

Infect. Immun.

Infect. Immun.

Arch. Dis. Child.

Annu. Rev. Nutr.

Regular Article
Bovine Lactoferrin Stimulates the Phagocytic Activity of Human Neutrophils: Identification of Its Active Domain