Functions of lactoferrin In
neonatal host defense
By
Tamer Ibrahim
Direct Anti-Microbial Effects
The anti-microbial effects attributed to Lf were initially believed to
be entirely due to the ability of unsaturated Lf to avidly bind iron and
thereby cause bacteriostatic effects in iron-requiring pathogens.
Iron-dependent anti-microbial effects of human and bovine Lf have
been observed against a number of pathogens, including [Link], S.
mutans, V. cholerae, and also P. aeruginosa, where iron chelation by
Lf was found to stimulate a form of cell motility that inhibited
biofilm formation by these bacteria.
Lf is bactericidal to several pathogens through interactions with the
lipopolysaccharide (LPS) of Gram negative and the lipotechoic acid of
Gram-positive bacteria.
In E. coli, Lf inhibits adherence and biofilm formation potentially by
binding to lipid portions of the LPS layer, with a resultant increase in
membrane permeability and disruption of virulence proteins anchored to
the outer membrane.
Lf has shown potent synergistic
activity in killing Gram-negative
bacteria in vitro with lysozyme—a
second important component of
the human milk whey fraction that
is able to degrade bacterial
membrane peptidoglycans. By
binding LPS and removing it from
the outer cell membrane, Lf allows
lysozyme to access and degrade
the inner membrane proteoglycans
and kill the bacteria
Against viruses, the attachment of Lf to surface proteoglycans, such as
heparan sulfate, to which Lf has a high affinity through its N-terminus
glycosaminoglycan-binding domains, thus blocking the entry of certain
viruses, e.g., HSV. Other mechanisms may involve direct interactions of
Lf with viral envelope proteins
In fungi such as Candida, Lf has been shown to have effects as well, and
was observed to cause cell wall perturbations, with the formation of
surface blebs, swelling, and the collapse of the cell.
Immunomodulatory Functions of Lactoferrin
Lf plays a key role in neonatal host defense by modulating the innate and
adaptive immune response of the neonate to infections
The effects of Lf on immune cells are modulated by binding to the
glycosaminoglycans on membrane peptidoglycans which are critical for the
binding of many cytokines and factors.
Other receptors described include lectins (e.g., TLR-4) which recognize the
glycan chains of Lf, receptors recognizing the Lfc or N1 domain,
intelectin-1 (found on enterocytes and immune cells), and nucleolin which
may serve the additional function of transporting Lf to the nucleus.
whereby Lf has been shown to activate cell cycle progression, proliferation,
and downstream cellular responses.
Innate Immune Effects of Lactoferrin
The effects of Lf on the innate immune response are related in part to its
ability to bind to pathogen-associated molecular patterns (PAMPs),
present on pathogens (e.g., LPS on Gram-negative bacteria and
peptidoglycans on Gram-positive bacteria).
Interfering the LPS-CD14 interaction to inhibit the release of pro
inflammatory cytokines e.g., TNF-α, IL-6, and IL-1β
Lf may also modulate recruitment of immune cells by interfering with the
expression of endothelial cell adhesion molecules required for the
recruitment of these cells to sites of inflammation
Activated neutrophils will release Lf from their secondary granules to
exert its direct microbicidal effects. Lf may also enhance the cytotoxic
functions of NK and lymphokine-activated killer cells, potentially
through binding to RNA and DNA
Lf receptors are found on macrophages and Lf is shown to activate
macrophages to release pro-inflammatory molecules e.g., TNF-α, IL-8,
and nitric oxide and to increase their phagocytic activity when infected
Lf is also expressed on the membranes of resting PMNs and may
enable interaction between Lf-bound microbes and PMNs .
Effects on Adaptive Immune Responses
Lf plays an important immunomodulatory role in activation and antigen
presentation by antigen-presenting cells (APCs) and in their functions in the
adaptive immune response by affecting T cell development.
Lf enhances the ability of macrophages to act asPCs by stimulating the
production of cytokines, such as IL-12, responsible for modulating
development of Th1 cell
Studies indicate that DCs differentiated in the presence of Lf showed decreased
responsiveness towards TLR ligands reduced cytokine production
demonstrating a potential role for Lf in immune homeostasis. These results
indicate a potent anti-inflammatory function
Lf is able to promote the maturation of immature B lymphocytes, shown
by an increase in surface Ig D and complement receptor expression
as well as proliferation in the Peyer’s patches of the intestine, suggesting
that Lf may act as an immunostimulatory factor on the mucosal immune
system
Summary
Unanswered ,pending questions on LF use :
Thank you
