Anticarcinogenesis pathways activated by bovine lactoferrin in the murine small intestine
Anticarcinogenesis pathways activated by bovine lactoferrin in the murine small intestine
复制标题
DOI：
10.1016/j.biochi.2008.06.012
复制
发表时间：
2009-01-01
期刊：
影响因子：
3.9
通讯作者：
Tsuda, Hiroyuki
中科院分区：
文献类型：
--
作者：
Iigo, Masaaki;Alexander, David B.;Tsuda, Hiroyuki
口服牛乳铁蛋白（bLF）可抑制大鼠结肠和其他器官的癌变，以及小鼠的肺转移。bLF介导其抗癌作用的可能机制是通过增强细胞因子的表达和随后的免疫细胞激活。口服bLF可增强小鼠小肠黏膜白细胞介素-18 (IL-18) mRNA的表达。重要的是，牛乳铁蛋白的胃蛋白酶水解物（bLFH）还能诱导小鼠小肠中IL-18 mRNA的表达，而由胃蛋白酶消化牛乳铁蛋白（bLFcin）产生的肽能诱导器官培养中成熟IL-18的表达。除IL-18外，bLF和bLFcin均诱导腹腔巨噬细胞和器官培养中caspase-1活性显著升高。巨噬细胞中成熟IL-18的增加被caspase-1抑制剂所抑制：caspase-1被认为可以切割IL-18的形式，产生活性的成熟IL-18。最后，bLF还能诱导腹腔巨噬细胞表达IFN γ。重要的是，在IFN γ敲除（GKO）小鼠中，bLF导致caspase-1蛋白表达增加，但未观察到IL-18 mRNA、caspase-1活性和成熟IL-18的诱导。这些结果表明，口服bLF可以诱导小肠中IFN γ和caspase-1的表达。IFN γ反过来增加靶基因的表达，包括IL-18。然后活性caspase-1裂解pro-IL-18生成成熟的IL-18。因此，bLF激活了由IFN γ、caspase-1和IL-18介导的效应通路。我们还表明，摄入的bLF能够激活不止一种效应途径。例如，在GKO小鼠中，虽然bLF不能激活IFN γ /caspase-1/IL-18效应通路，但它能够通过激活IFN α /IL-7效应通路来抑制肿瘤的生长和转移。(C) 2008 Elsevier Masson SAS。版权所有。
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 IFN gamma by peritoneal macrophages. Importantly, in IFN gamma 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 IFN gamma and caspase-1 in the small intestine. IFN gamma 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 IFN gamma, 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 IFN gamma/caspase-1/IL-18 effector pathway, it was able to inhibit tumor growth and metastasis by activation of an IFN alpha/IL-7 effector pathway. (C) 2008 Elsevier Masson SAS. All rights reserved.