Bovine Lactoferrin Counteracts Toll-Like Receptor Mediated Activation Signals in Antigen Presenting Cells

Abstract

Lactoferrin (LF), a key element in mammalian immune system, plays pivotal roles in host defence against infection and excessive inflammation. Its protective effects range from direct antimicrobial activities against a large panel of microbes, including bacteria, viruses, fungi and parasites, to antinflammatory and anticancer activities. In this study, we show that monocyte-derived dendritic cells (MD-DCs) generated in the presence of bovine LF (bLF) fail to undergo activation by up-modulating CD83, co-stimulatory and major histocompatibility complex molecules, and cytokine/chemokine secretion. Moreover, these cells are weak activators of T cell proliferation and retain antigen uptake activity. Consistent with an impaired maturation, bLF-MD-DC primed T lymphocytes exhibit a functional unresponsiveness characterized by reduced expression of CD154 and impaired expression of IFN-γ and IL-2. The observed imunosuppressive effects correlate with an increased expression of molecules with negative regulatory functions (i.e. immunoglobulin-like transcript 3 and programmed death ligand 1), indoleamine 2,3-dioxygenase, and suppressor of cytokine signaling-3. Interestingly, bLF-MD-DCs produce IL-6 and exhibit constitutive signal transducer and activator of transcription 3 activation. Conversely, bLF exposure of already differentiated MD-DCs completely fails to induce IL-6, and partially inhibits Toll-like receptor (TLR) agonist-induced activation. Cell-specific differences in bLF internalization likely account for the distinct response elicited by bLF in monocytes versus immature DCs, providing a mechanistic base for its multiple effects. These results indicate that bLF exerts a potent anti-inflammatory activity by skewing monocyte differentiation into DCs with impaired capacity to undergo activation and to promote Th1 responses. Overall, these bLF-mediated effects may represent a strategy to block excessive DC activation upon TLR-induced inflammation, adding further evidence for a critical role of bLF in directing host immune function.

Lactoferrin: Balancing Ups and Downs of Inflammation Due to Microbial Infections

“…The mechanisms of Lf action on the inflammatory response have been analyzed in regarding to the ability of Lf to interact with LPS and block its interaction with TLR4 in in vitro cultures of intestinal cell lines and murine peritoneal or cell line macrophages [156,157,166,167,168,169,170]. These assays have evidenced that Lf down- or up-modulates LPS-mediated inflammatory response via dependent or independent TLR4/NF-κB signal pathway.…”

“…Similarly, in human monocyte cell lines (THP-1 and Mono Mac 6), hLf also displayed down-modulatory activity on LPS-associated cytokine response by blocking the binding of NF-κB to the TNFα promoter [170]. Assays in cultures of human peripheral blood mononuclear cells showed that bLf displayed an anti-inflammatory response by driving the differentiation of LPS-treated monocytes toward dendritic cells with low capacity of both differentiation and elicitation of Th1 response by counteracting the TLR4 mediated activation signals [167]. On the other hand, up-modulatory impact of Lf on inflammatory effects of LPS was documented in assays of RAW 264.7 macrophage cell line and peritoneal macrophages, indicating that bLf, in the form of complex with LPS, enhanced cytokine response of TNFα, IL-1 and IL-6 via TLR4–NF-κB signal pathway [168].…”

Structural Characterization of the Interaction of Human Lactoferrin with Calmodulin

“…Specific, saturable Lf receptors (LfRs) have been detected on the plasma membrane of several cell types including enterocytes, bronchial epithelial, brain, mammary gland, monocytes, macrophages, lymphocytes, mast, and cytotrophoblasts [85], [86], [87], [88], [89], [90], [91]. Upon binding apo- or Fe 3+ -Lf, the Lf:LfR complex is internalized through clathrin-mediated endocytosis and in a number of cell types, targeted to the nucleus through the N-terminal subdomain of the N-lobe [20], [21], [92], [93], [94], [95]. The nuclear localization of Lf suggests a role in transcriptional regulation and indeed, Lf has been shown to trans -activate AP-1 and NFκB, two transcription factors that play central roles in the inflammatory response, and control of cell division, differentiation and apoptosis [15], [18], [89], [93], [96].…”

Redox state markers of tumors in patients with colorectal cancer

“…Поряд із цим, активнопроліферуючі пухлинні клітини потребу-ють значної кількості заліза. Ось чому в пухлинній тканині часто реєструють підвищені рівні фери-тину, ЛФ, ТФ та його рецепторів [7][8][9].…”