Bovine Lactoferrin Modulates Dendritic Cell Differentiation and Function

Olaf Perdijk,Erik Van Den Brink,Huub Savelkoul,Sylvia Brugman,R Van Neerven

doi:10.3390/nu10070848

Olaf Perdijk, Erik Van Den Brink + Show 3 more

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https://doi.org/10.3390/nu10070848

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Abstract

Lactoferrin is an abundant glycoprotein in bovine milk that has immunomodulatory effects on human cells. Bovine lactoferrin (LF) binds lipopolysaccharides (LPS) with high affinity and is postulated to act via TLR4-dependent and -independent mechanisms. It has been shown that LF modulates differentiation of human monocytes into tolerogenic dendritic cells. However, in a previous study, we showed that LPS also mediates differentiation into tolerogenic dendritic cells (DC). Since LF binds LPS with high affinity, it remains to be investigated whether LF or LPS is mediating these effects. We, therefore, further investigated the LPS-independent effect of LF on differentiation of human monocytes into dendritic cells (DC). Human monocytes were isolated by magnetic cell sorting from freshly isolated PBMCs and cultured for six days in the presence of IL-4 and GM-CSF with or without LF or proteinase K treated LF to generate DC. These immature DC were stimulated for 48 h with LPS or Poly I:C + R848. Cell surface marker expression and cytokine production were measured by flow cytometry. DC differentiated in the presence of LF produced higher IL-6 and IL-8 levels during differentiation and showed a lower expression of CD1a and HLA-DR. These LFDCs showed to be hyporesponsive towards TLR ligands as shown by their semi-mature phenotype and reduced cytokine production. The effect of LF was abrogated by proteinase K treatment, showing that the functional effects of LF were not mediated by LPS contamination. Thus, LF alters DC differentiation and dampens responsiveness towards TLR ligands. This study indicates that LF can play a role in immune homeostasis in the human GI tract.

Highlights

Bovine lactoferrin (LF) is an abundant glycoprotein in cow’s milk that is 69% identical to human lactoferrin at the protein level [1]
Monocytes were differentiated into monocyte-derived dendritic cells (DC) in the presence or absence of LF
MoDC stimulated with LF or LF + Poly I:C and

Summary

Introduction

Bovine lactoferrin (LF) is an abundant glycoprotein in cow’s milk that is 69% identical to human lactoferrin at the protein level [1]. The involved anti-pathogenic mechanisms, which are mostly investigated in vitro, range from depriving iron, antimicrobial activity by bioactive peptides and decoy receptor activity. These mechanisms may underlie the protective effect against sepsis by LF supplementation in very low birth weight (VLBW) infants [3,4,5,6,7]. Subsequent analysis of this study showed that LF inhibits the progression of invasive fungal infections [4], indicating immunomodulatory effects of LF In line with these findings, LF was shown to induce the prevalence of regulatory T cells in VLBW infants [6].

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