Activation of Intestinal Mucosal Immunity in Tumor‐bearing Mice by Lactoferrin

We have previously demonstrated that oral administration of bovine lactoferrin (bLF) markedly increases CD4(+) and CD8(+) T cells and NK (asialoGM1(+)) cells in the blood of tumor‐bearing mice and enhances anti‐metastatic activity. In this paper, we document that oral administration of bLF and bLF‐hydrolysate (bLFH) is associated with strong increases in CD4(+) and CD8(+) T, as well as asialoGM1(+) cells in lymphoid tissues and lamina propria of the small intestine in mice, especially in tumor‐bearing animals in which Co26Lu cells were implanted subcutaneously. Moreover, IgM(+) and IgA(+) B cells in lamina propria of the small intestine were also significantly increased by bLF and bLFH. Bovine apo‐transferrin (bTF) did not exhibit such activity. In the colon, only CD8(+) cells were significantly increased by treatment with bLF, while asialoGM1(+) cells were significantly decreased. bLF and bLFH induced cytokines to activate T, B and asialoGM1(+) cells. Administration of bLF and bLFH, but not bTF, increased production of interleukin‐18 (IL‐18), interferon‐gamma (IFN‐γ) and caspase‐1 in the mucosa of the small intestine. Particularly high levels of IL‐18 were found in the epithelial cells of the small intestine. Moreover, administration of bLF and bLFH, but not bTF, induced IFN‐γ presenting cells in the small intestine. Caspase‐1, which processes proIL‐18 to mature IL‐18, was also induced in the epithelial cells of the small intestine following treatment with bLF and bLFH, but not with bTF. These results suggest that enhanced production of IL‐18 and IFN‐γ and caspase‐1 induction by treatment with bLF may be important for elevation of intestinal mucosal immunity.