Oral Administration of Lactoferrin Increases NK Cell Activity in Mice via Increased Production of IL-18 and Type I IFN in the Small Intestine

Abstract

Evidence that lactoferrin (LF) influences various immune functions is now accumulating. Recent reports have shown that bovine LF (BoLF) enhances antimicrobial, antiviral, and antitumor immune activities when orally administered. Here, we report that orally administered BoLF increases natural killer (NK) cell populations in peripheral blood and spleen in a dose-dependent manner and enhances interferon-gamma (IFN-gamma) production by NK cells. Using intraperitoneal (i.p.) injection of poly(I:C) to induce NK cell trafficking into the peritoneum, oral BoLF increased NK cell migration. Oral BoLF also produced an immediate increase in the levels of interleukin-18 (IL-18) in the portal circulation. In IL-18 knockout (KO) mice, BoLF did not increase the numbers of NK cells, although NK cell cytotoxic activity and poly(I:C)-induced trafficking activity were both enhanced by oral BoLF, even in IL-18 KO mice. Furthermore, oral BoLF increased the expression of IFN-alpha and IFN-beta in Peyer's patches (PP) and mesenteric lymph nodes (MLN). Oral administration of 2- chloroadenosine selectively depleted the PP cells and blocked the ability of oral BoLF to increase NK cell accumulation in the peritoneum following poly(I:C) i.p. injection. Collectively, these results demonstrate that orally administered BoLF stimulates intestine-associated immune functions, including the production of IL- 18 and type I IFNs and increased NK cell activity.

Inhibitory effects of orally administrated liposomal bovine lactoferrin on the LPS-induced osteoclastogenesis

“…35 Orally administrated bLF stimulated intestineassociated immune functions including the production of IL-18 and IFN and increased NK cell activity. 36 Macrophages, Effect of lactoferrin on osteoclastogenesis E Yamano et al with low ability to produce TNF-a, internalized bLF at the Payer's patch, may infiltrate into LPS-applied periodontal tissue through the circulatory system in the L-bLF group. The downregulation of TNF-a production from these macrophages resulted in the inhibition of bone resorption.…”

Lactoferrin Acts as an Alarmin to Promote the Recruitment and Activation of APCs and Antigen-Specific Immune Responses

“…We consider that doses around 100 g/ml might have relevant clinical importance, because of their critical effect on the survival and activation of APCs, and this should be taken into consideration for future vaccines or treatments. As lactoferrin levels in milk, and especially in colostrum, are also very high, it is possible that lactoferrin also promotes development of the newborn immune system by activating APCs positioned along the gastrointestinal tract, in addition to its antimicrobial capacities and the effect exerted on the intestinal epithelium (46).…”

Soybean protein fraction digested with neutral protease preparation, “Peptidase R”, produced by Rhizopus oryzae, stimulates innate cellular immune system in mouse

“…For example, the oral administration of CPP preparation enhanced mucosal IgA responses in piglets [10], and a piglet fed with CPP preparation has been sold in Japan. The oral administration of lactoferrin enhanced IFN-γ production in mice [36], and some foods and feeds have been sold for the purpose of preventing infectious diseases in animals. In this work, the authors found that Ro-digest prepared from soybean protein hydrolyzed by Peptidase R (R. oryzae) stimulated cellular immune systems, in particular, the innate immunity in mice.…”