Orally administered bovine lactoferrin induces caspase-1 and interleukin-18 in the mouse intestinal mucosa: a possible explanation for inhibition of carcinogenesis and metastasis.
We have previously demonstrated that oral administration of bovine lactoferrin (bLF) markedly inhibits lung metastatic colony formation, and that this inhibition was possibly due to the activation of T and NK cells. Furthermore, we found that interleukin-18 (IL-18) is induced in epithelial cells of the small intestine by bLF. The present study was undertaken to confirm cytokine production in response to bLF and to assess the underlying mechanisms. Markedly elevated IL-18 levels were found in the small intestine 1-3 h after a single administration of bLF, its pepsin hydrolysate (bLFH), or bTF. Importantly, while IL-18 was significantly increased after a regimen of seven daily administrations of bLF or bLFH, administration of bTF over the course of seven days had little or no effect. In addition to IL-18, a significant increase in caspase-1 activity and interferon-gamma (IFN-gamma) was found in the small intestine after administration of bLF. Similarly, in peritoneal macrophages, bLF markedly enhanced caspase-1 activity and IL-18 levels. Finally, a caspase-1 inhibitor significantly decreased bLF mediated induction of IL-18 in vitro. (bTF had no effect on either caspase-1 or IFN-gamma or on IL-18 in vitro.) These results demonstrate the possibility that elevation of caspase-1 activity by bLF and its hydrolysate may be important for production of mature IL-18 in vivo, and thus in potentiating the killing activity of T and NK cells against tumor cells.
Iigo
Masaaki
M
Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. miigou@gan2.ncc.go.jp
Shimamura
Mariko
M
Matsuda
Eiji
E
Fujita
Ken-ichi
K
Nomoto
Hiroshi
H
Satoh
Jun
J
Kojima
Syuji
S
Alexander
David B
DB
Moore
Malcolm A
MA
Tsuda
Hiroyuki
H
D000284:Administration, Oral; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D020170:Caspase 1 / Q000187:drug effects / Q000378:metabolism*; D061945:Caspase Inhibitors; D002417:Cattle; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D006868:Hydrolysis; D007371:Interferon-gamma / Q000097:blood / Q000378:metabolism; D020382:Interleukin-18 / Q000097:blood / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D007781:Lactoferrin / Q000008:administration & dosage* / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010434:Pepsin A / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D020382:Interleukin-18; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; D007371:Interferon-gamma; D007781:Lactoferrin; D020170:Caspase 1; D010434:Pepsin A