TNF-α mediates macrophage-induced bystander effects through Netrin-1.
TNF-α mediates macrophage-induced bystander effects through Netrin-1.
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DOI：
10.1158/0008-5472.can-12-1463
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发表时间：
2012-10-15
期刊：
影响因子：
11.2
通讯作者：
Huycke MM
中科院分区：
文献类型：
--
作者：
Yang Y;Wang X;Moore DR;Lightfoot SA;Huycke MM
巨噬细胞诱导的旁观者效应被认为是人类肠道共生菌粪肠球菌引发的染色体不稳定和结肠癌的重要介质。人们对炎症细胞因子如何介导旁观者效应知之甚少，但这一领域的问题很重要，因为炎症过程对癌症的发生和发展起着关键作用。在这里，我们报道了中枢促炎细胞因子TNF-α作为巨噬细胞诱导的旁观者效应的扩散性介质，巨噬细胞的增殖引发上皮细胞产生Netrin-1，一种神经元引导分子。TNF-α-介导的旁观者试验采用小鼠原代结肠上皮细胞和粪肠杆菌感染的巨噬细胞（体外）共培养系统，并采用il -10缺陷小鼠结肠癌模型，该模型涉及粪肠杆菌的长期定植（体内）。在细胞共培养中，我们观察到TNF-α受体Tnfrsf1b和Netrin-1的表达增加。这些作用可被抗tnf -α抗体或NF-κB信号抑制剂预处理阻断。rnai介导的Tnfrsf1b的衰减降低了TNF-α-诱导的netrin-1的产生，增强了上皮细胞的凋亡。进一步观察，粪肠杆菌定殖的IL-10−/−小鼠结肠活检显示隐窝增生，巨噬细胞、TNF-α、netrin-1、NF-κB、Tnfrsf1b和增殖标记物PCNA的染色增加，上皮细胞凋亡也减少。总之，我们的研究结果确定了巨噬细胞诱导的旁观者效应的途径，其中TNF-α触发TNFRSF1b受体信号传导，导致Netrin-1的产生增加，隐窝增生和上皮细胞凋亡减少。在阐明肠道微环境中重要的评论相关促炎机制时，我们的工作强调了Netrin-1和特定TNF-α受体作为预防或治疗结直肠癌的候选靶点的作用。
Macrophage-induced bystander effects have been implicated as an important mediator of chromosomal instability and colon cancer triggered by Enterococcus faecalis a human intestinal commensal bacteria. There is little understanding about how inflammatory cytokines mediate bystander effects, but questions in this area are important because of the pivotal contributions made by inflammatory processes to cancer initiation and progression. Here we report that the central pro-inflammatory cytokine TNF-α acts as a diffusible mediator of the bystander effects induced by macrophages, an effect caused by a proliferation of macrophages that trigger epithelial cell production of Netrin-1, a neuronal guidance molecule. TNF-α-mediated bystander assays employed a murine co-culture system of primary colonic epithelial cells and E. faecalis-infected macrophages (in vitro), with an IL-10-deficient mouse model of colon cancer that involves long-term colonization with E. faecalis (in vivo). In cell co-cultures, we observed increased expression of the TNF-α receptor Tnfrsf1b and Netrin-1. These effects were blocked by anti-TNF-α antibody or by pretreatment with an inhibitor of NF-κB signaling. RNAi-mediated attenuation of Tnfrsf1b decreased TNF-α-induced netrin-1 production and augmented epithelial cell apoptosis in culture. Extending these observations, colon biopsies from E. faecalis-colonized IL-10−/− mice exhibited crypt hyperplasia and increased staining for macrophages, TNF-α, netrin-1, NF-κB, Tnfrsf1b and the proliferation marker PCNA, also displaying a reduction in epithelial cell apoptosis. Together, our results define a pathway for macrophage-induced bystander effects in which TNF-α triggers TNFRSF1b receptor signaling leading to increased production of Netrin-1, crypt hyperplasia and decreased epithelial cell apoptosis. In elucidating an important commensal-associatedpro-inflammatory mechanism in the intestinal microenvironment, our work highlights the role of Netrin-1 and a specific TNF-α receptor as candidate targets to prevent or treat colorectal cancer.