Seidelin Jakob B
a Department of Gastroenterology, Medical Section , Herlev Hospital, University of Copenhagen , Herlev , Denmark.
Scand J Gastroenterol. 2015;50 Suppl 1:1-29. doi: 10.3109/00365521.2016.1101245.
Ulcerative colitis is an inflammatory bowel disease involving the colon resulting in bloody diarrhea and increased risk of colorectal cancer in certain patient subgroups. Increased apoptosis in the epithelial cell layer causes increased permeability, especially during flares; this leads to translocation of luminal pathogens resulting in a continued inflammatory drive. The present work investigates how epithelial apoptosis is regulated in ulcerative colitis. The main results are that Fas mediated apoptosis is inhibited during flares of ulcerative colitis, probably by an upregulation of cellular inhibitor of apoptosis protein 2 (cIAP2) and cellular FLICE-like inhibitory protein. cIAP2 is upregulated in regenerative epithelial cells both in ulcerative colitis and in experimental intestinal wounds. Inhibition of cIAP2 decreases wound healing in vitro possibly through inhibition of migration. Altogether, it is shown that epithelial cells in ulcerative colitis responds to the hostile microenvironment by activation of cytoprotective pathways that tend to counteract the cytotoxic effects of inflammation. However, the present studies also show that epithelial cells produce increased amounts of reactive oxygen species during stimulation with tumor necrosis factor-α and interferon-γ resulting in DNA instability. The combined effect of increased DNA-instability and decreased apoptosis responses could lead to neoplasia.
溃疡性结肠炎是一种累及结肠的炎症性肠病，会导致血性腹泻，在某些患者亚组中还会增加患结直肠癌的风险。上皮细胞层中凋亡增加会导致通透性增加，尤其是在疾病发作期间；这会导致腔内病原体易位，从而持续引发炎症。本研究调查了溃疡性结肠炎中上皮细胞凋亡是如何被调节的。主要结果是，在溃疡性结肠炎发作期间，Fas介导的凋亡受到抑制，这可能是由于细胞凋亡抑制蛋白2（cIAP2）和细胞FLICE样抑制蛋白的上调所致。cIAP2在溃疡性结肠炎和实验性肠道伤口的再生上皮细胞中均上调。抑制cIAP2可能通过抑制迁移来降低体外伤口愈合。总之，研究表明，溃疡性结肠炎中的上皮细胞通过激活细胞保护途径对恶劣的微环境做出反应，这些途径往往会抵消炎症的细胞毒性作用。然而，目前的研究还表明，上皮细胞在受到肿瘤坏死因子-α和干扰素-γ刺激时会产生更多的活性氧，导致DNA不稳定。DNA不稳定性增加和凋亡反应降低的综合作用可能会导致肿瘤形成。
