Ben May Department for Cancer Research, Johns Hopkins Medical Institute, Baltimore, Maryland, USA.
Inflamm Bowel Dis. 2010 Jun;16(6):1063-70. doi: 10.1002/ibd.21195.
CD95 is a member of the tumor necrosis factor receptor family. It is constitutively expressed on the basolateral membrane of intestinal epithelial cells (IECs) and under certain conditions induces apoptosis when crosslinked by its natural ligand, CD95L. A multitude of studies have been published addressing the question of where and under which conditions CD95L is produced in the gut in normal, inflammatory, and neoplastic situations and whether the apoptosis-inducing activity of CD95 contributes to pathology. Although some of these studies have considerably influenced our view on the role of the CD95/CD95L system compelling evidence for an involvement of the CD95/CD95L system in the physiological epithelial cell turnover is lacking.
CD95 signaling deficiency in the colon was achieved in 2 ways. By transplanting bone marrow from wildtype mice into lethally irradiated mice expressing a signaling deficient mutant of CD95 (lpr(cg) mice) and by tissue-specific deletion of CD95 in IECs. Mice were treated with either 3 cycles of dextran sulfate sodium (DSS) to induce colitis or by injection of azoxymethane (AOM) followed by 3 cycles of DSS to induce colon cancer. Disease index and the formation of neoplastic lesions in the colon were determined and histological analysis was performed.
In each mouse model lacking CD95 activity in the colon mice were hypersensitive to DSS-induced colitis. In the CD95-deficient mice this did not have an effect on AOM/DSS-induced cancer formation.
CD95 plays a role in protecting the colon from inflammation without contributing to colon cancer, under conclusions of increased inflammation.
CD95 是肿瘤坏死因子受体家族的一员。它在肠上皮细胞 (IECs) 的基底外侧膜上持续表达，并且在某些条件下，当其天然配体 CD95L 交联时，会诱导细胞凋亡。已经发表了大量研究来解决 CD95L 在正常、炎症和肿瘤情况下在肠道中何处以及在何种条件下产生的问题，以及 CD95 诱导凋亡的活性是否对病理学有贡献。尽管其中一些研究极大地影响了我们对 CD95/CD95L 系统作用的看法，但缺乏令人信服的证据表明 CD95/CD95L 系统参与了生理上皮细胞更新。
通过将来自野生型小鼠的骨髓移植到表达信号缺陷型 CD95 突变体的致死性辐射小鼠 (lpr(cg) 小鼠) 中以及在 IECs 中特异性缺失 CD95 两种方式在结肠中实现 CD95 信号缺失。用葡聚糖硫酸钠 (DSS) 处理小鼠 3 个周期以诱导结肠炎，或用偶氮甲烷 (AOM) 注射后再用 DSS 处理 3 个周期以诱导结肠癌。确定疾病指数和结肠中肿瘤病变的形成，并进行组织学分析。
在缺乏结肠中 CD95 活性的每种小鼠模型中，缺乏 CD95 活性的小鼠对 DSS 诱导的结肠炎更为敏感。在缺乏 CD95 的小鼠中，这对 AOM/DSS 诱导的癌症形成没有影响。
CD95 在保护结肠免受炎症而不促进结肠癌方面发挥作用，在炎症增加的结论下。
