title: Anticarcinogenesis pathways activated by bovine lactoferrin in the murine small intestine.
abstract: Oral administration of bovine lactoferrin (bLF) inhibits carcinogenesis in the colon and other organs in rats, and lung metastasis in mice. A likely mechanism by which bLF mediates its anticarcinogenesis effects is by enhanced expression of cytokines and subsequent activation of immune cells. Oral administration of bLF enhances expression of interleukin-18 (IL-18) mRNA in the mucosa of the small intestine of mice. Importantly, the pepsin hydrolysate of bLF (bLFH) also induced expression of IL-18 mRNA in the mouse small intestine and a peptide produced by pepsin digestion of bLF, bovine lactoferricin (bLFcin), induced expression of mature IL-18 in organ culture. In addition to IL-18, bLF and bLFcin both induced significant increases in caspase-1 activity in peritoneal macrophages and in organ cultures. The increase of mature IL-18 by macrophages was inhibited by caspase-1 inhibitor: caspase-1 is known to cleave the proform of IL-18 to produce active mature IL-18. Finally, bLF also induced expression of IFNgamma by peritoneal macrophages. Importantly, in IFNgamma knockout (GKO) mice, bLF administration resulted in increased expression of caspase-1 protein, but induction of IL-18 mRNA, caspase-1 activity, and mature IL-18 was not observed. These results indicate that orally administered bLF can induce expression of IFNgamma and caspase-1 in the small intestine. IFNgamma in turn increases expression of target genes, including IL-18. Active caspase-1 then cleaves pro-IL-18 to generate mature IL-18. Thus, bLF activates an effector pathway mediated by IFNgamma, caspase-1, and IL-18. We also show that ingested bLF is able to activate more than a single effector pathway. For example, in GKO mice while bLF administration could not activate the IFNgamma/caspase-1/IL-18 effector pathway, it was able to inhibit tumor growth and metastasis by activation of an IFNalpha/IL-7 effector pathway.
authors.affiliation: Cancer Prevention Basic Research Project, National Cancer Center Research Institute, Tsukiji, Chuo-ku, Tokyo.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Iigo
authors.forename: David B
authors.initials: DB
authors.lastname: Alexander
authors.forename: Ne
authors.initials: N
authors.lastname: Long
authors.forename: Jiegou
authors.initials: J
authors.lastname: Xu
authors.forename: Katsumi
authors.initials: K
authors.lastname: Fukamachi
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Futakuchi
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Takase
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuda
mesh_terms: D000818:Animals; D015153:Blotting, Western; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D061945:Caspase Inhibitors; D002417:Cattle; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D019409:Interleukin-15 / Q000235:genetics; D020382:Interleukin-18 / Q000235:genetics; D015851:Interleukin-7 / Q000235:genetics; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism*; D007781:Lactoferrin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009369:Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D016133:Polymerase Chain Reaction
chemical_list: D061945:Caspase Inhibitors; D016207:Cytokines; D019409:Interleukin-15; D020382:Interleukin-18; D015851:Interleukin-7; C082171:lactoferricin B; D007781:Lactoferrin; D020170:Caspase 1