Lactoferrin, a major defense protein of innate immunity, is a novel maturation factor for human dendritic cells

Abstract

Lactoferrin (LF) is an important protein component of the innate immune system that is broadly distributed within the body fluids. LF is endowed with multiple biological activities. Talactoferrin (TLF), a recombinant human LF, is in clinical development as an anticancer agent and is entering Phase III clinical trials. Here, we show that TLF induces the maturation of human dendritic cells (DCs) derived from monocytes. TLF, at physiologically relevant concentrations (100 microg/ml) up-regulates the expression of human leukocyte antigen (HLA) class II, CD83, CD80, and CD86 costimulatory molecule and CXCR4 and CCR7 chemokine receptors, acting primarily through the p38 MAPK signaling pathway. DCs matured by TLF displayed an enhanced release of IL-8 and CXCL10, as well as a significantly reduced production of IL-6, IL-10, and CCL20. They also display a reduced ability to take up antigen and increased capacity to trigger proliferation and release IFN-gamma in the presence of allogeneic human T cells. TLF-matured DCs are able to prime naive T cells to respond to KLH antigen and display a significantly increased capacity to present Flu-MA(58-66) peptide to HLA-A2-matched T cells. These data suggest that a key immunomodulatory function that may be mediated by TLF is to link the innate with adaptive immunity through DC maturation.

Adenovirus serotype 5 infects human dendritic cells via a coxsackievirus–adenovirus receptor-independent receptor pathway mediated by lactoferrin and DC-SIGN

“…Lf is present in mucosal tissues and in most bodily fluids, such as milk, tear fluid, saliva, nasal secretions and vaginal mucus, and at low concentration in serum (Masson et al, 1966;Weinberg, 2001). Lf is of interest with regard to DCs as it can interact directly with these cells and modulate important functions such as migration, cell activation and induction of T-cell responses (de la Rosa et al, 2008;Puddu et al, 2009;Spadaro et al, 2008). It is therefore likely that Lf is present at high concentration at anatomical sites where peripheral DCs encounter pathogens such as Ad5 in vivo.…”

“…Interestingly, Lf is mainly known for its immunomodulatory properties, which enhance anti-microbial and anti-inflammatory responses (Legrand et al, 2005). High levels of Lf present during inflammation were recently shown to directly recruit and activate DCs (de la Rosa et al, 2008;Spadaro et al, 2008).…”

Evaluation of the Bioactivity of Recombinant Human Lactoferrins Toward Murine Osteoblast-Like Cells for Bone Tissue Engineering

“…2 The diverse list of LF's multifunctional roles includes immunomodulatory, anticancer, antibacterial, and antiviral properties. 3,4 Some of the recent studies have demonstrated LF as an effector molecule in the skeleton, 5,6 due to its ability to increase osteoblast proliferation, survival, and differentiation [6][7][8] and decrease osteoclast survival. 9,10 Many of the biological activities of LF have been attributed to its ability to induce signal transduction pathways through cell surface receptors.…”

Immunotherapy: is a minor god yet in the pantheon of treatments for lung cancer?

“…Negative data emerged also from clinical trials with PF-3512676, a synthetic TLR9-activating oligodeoxynucleotide, which works as the natural ligand of TLR9 which enhances maturation of DCs [72,73]. Also, lactoferrin, which is an iron-binding glycoprotein found in breast milk, has shown several immunomodulatory functions [74]. Talactoferrin-a is the recombinant human variant of lactoferrin, purified from Aspergillus niger var.…”