RRC ID 67949
Author Iigo M, Alexander DB, Long N, Xu J, Fukamachi K, Futakuchi M, Takase M, Tsuda H.
Title Anticarcinogenesis pathways activated by bovine lactoferrin in the murine small intestine.
Journal Biochimie
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.
Volume 91(1)
Pages 86-101
Published 2009-1-1
DOI 10.1016/j.biochi.2008.06.012
PII S0300-9084(08)00203-4
PMID 18634843
MeSH Animals Blotting, Western Caspase 1 / genetics Caspase 1 / metabolism Caspase Inhibitors Cattle Cells, Cultured Cytokines / metabolism Enzyme-Linked Immunosorbent Assay Female Gene Expression / drug effects Immunohistochemistry In Vitro Techniques Interleukin-15 / genetics Interleukin-18 / genetics Interleukin-7 / genetics Intestinal Mucosa / drug effects Intestinal Mucosa / metabolism Intestine, Small / drug effects* Intestine, Small / metabolism* Lactoferrin / administration & dosage Lactoferrin / pharmacology* Male Mice Mice, Inbred BALB C Mice, Knockout Neoplasms / metabolism Neoplasms / prevention & control* Polymerase Chain Reaction
IF 3.413
Human and Animal Cells RAW 264(RCB0535)