炎症性肠炎，比如大肠溃疡炎症，严重影响了全世界超过400万人的生活，而有效的治疗这些疾病需要从分子机理研究入手。最近，来自德国科隆大学和美因兹大学的研究人员，在意大利的欧洲分子生物学实验室，破译了引发慢性肠道炎症的分子学密码。这项研究已经发表在最近的《自然》杂志网络版，揭示了一个在老鼠身上测试的单独分子引发肠道炎症的一些分子机理，它可以作为研究人类炎症性肠病的基础。
我们的内脏可以看做大量细菌的家，它们与人类和平共处并且能够帮助食物消化，如果它们渗透过肠壁，那么这些细菌可能会造成危害并且引发疾病。这就是为一些薄薄的、连续性的细胞层（上皮细胞）连接在肠道的表面创造了一个壁垒，防止细菌通过这个界限。这种机制控制上皮细胞的完整性并且保持身体健康，但是尚未完全清楚其机理。
来自科隆大学的墨西哥小组成员Arianna Nency以及美因兹大学的Christoph Becker研究了NF-kB的作用，该特征分子保住细胞压力。在对上皮细胞的研究中，科学家建立了不会表达NEMO的老鼠模型，这是一种会与NF-kB发生反映的蛋白质，存在于上皮细胞当中。结果，这些老鼠患上和人类非常类似的大肠炎。仔细观察这些老鼠发现，它们的上皮细胞被破坏了。NF-kB是细胞生存的信号，如果没有它，预示着细胞已经死亡，这种现象已经发生在老鼠的肠道上，单个上皮细胞死亡会损害肠道内层。通过这个裂缝细菌会渗透至肠道，而与之相联系的免疫系统是体内最强大的免疫系统，它会对入侵者发出强烈的免疫信号，在与细菌进行斗争的过程中，我们的上皮细胞会分泌一种信号带来发炎的症状。这将是一种恶性循环，炎症信号能够到达上皮细胞，而上皮细胞对于缺乏NF-kB非常敏感，缺乏它将导致死亡，更多的上皮细胞死亡将构成肠道表皮上更大的裂缝，这将导致更多的细菌进入，结果是免疫系统对此进行持续不断的免疫反应，导致我们所知道的肠道炎症疾病的发生。
关于肠道上皮细胞NF-kB信号缺乏导致炎症这一现象的研究，提供了一个新的炎症性肠病发病机理。因为老鼠的免疫系统和人类的很相似，通过老鼠模型试验获得的结果，为解决引发人类炎症性肠病发病机理提供了一条崭新的思路。
部分英文原文：
Nature advance online publication 14 March 2007 | doi:10.1038/nature05698; Received 8 December 2006; Accepted 23 February 2007; Published online 14 March 2007
Epithelial NEMO links innate immunity to chronic intestinal inflammation
Arianna Nenci1,2,6, Christoph Becker3,6, Andy Wullaert1, Ralph Gareus1, Geert van Loo2, Silvio Danese4, Marion Huth2, Alexei Nikolaev3, Clemens Neufert3, Blair Madison5, Deborah Gumucio5, Markus F. Neurath3,6 and Manolis Pasparakis1,2
Institute for Genetics, University of Cologne, Zülpicher Strasse 47, 50674 Cologne, Germany
EMBL Mouse Biology Unit, I-00016 Monterotondo, Italy
Laboratory of Clinical Immunology, I. Department of Medicine, University of Mainz, Obere Zahlbacher Strasse 63, 55131 Mainz, Germany
Division of Gastroenterology, Istituto Clinico Humanitas-IRCCS in Gastroenterology, Viale Manzoni 56, 20089 Rozzano, Milan, Italy
Department of Cell & Developmental Biology, Center for Organogenesis, The University of Michigan, Ann Arbor, Michigan 48109-0616, USA
These authors contributed equally to this work.
Correspondence to: Manolis Pasparakis1,2 Correspondence and requests for materials should be addressed to M.P. (Email: pasparakis@uni-koeln.de).
Deregulation of intestinal immune responses seems to have a principal function in the pathogenesis of inflammatory bowel disease1, 2, 3, 4. The gut epithelium is critically involved in the maintenance of intestinal immune homeostasis—acting as a physical barrier separating luminal bacteria and immune cells, and also expressing antimicrobial peptides3, 5, 6. However, the molecular mechanisms that control this function of gut epithelial cells are poorly understood. Here we show that the transcription factor NF-B, a master regulator of pro-inflammatory responses7, 8, functions in gut epithelial cells to control epithelial integrity and the interaction between the mucosal immune system and gut microflora. Intestinal epithelial-cell-specific inhibition of NF-B through conditional ablation of NEMO (also called IB kinase- (IKK)) or both IKK1 (IKK) and IKK2 (IKK)—IKK subunits essential for NF-B activation7, 8, 9—spontaneously caused severe chronic intestinal inflammation in mice. NF-B deficiency led to apoptosis of colonic epithelial cells, impaired expression of antimicrobial peptides and translocation of bacteria into the mucosa. Concurrently, this epithelial defect triggered a chronic inflammatory response in the colon, initially dominated by innate immune cells but later also involving T lymphocytes. Deficiency of the gene encoding the adaptor protein MyD88 prevented the development of intestinal inflammation, demonstrating that Toll-like receptor activation by intestinal bacteria is essential for disease pathogenesis in this mouse model. Furthermore, NEMO deficiency sensitized epithelial cells to tumour-necrosis factor (TNF)-induced apoptosis, whereas TNF receptor-1 inactivation inhibited intestinal inflammation, demonstrating that TNF receptor-1 signalling is crucial for disease induction. These findings demonstrate that a primary NF-B signalling defect in intestinal epithelial cells disrupts immune homeostasis in the gastrointestinal tract, causing an inflammatory-bowel-disease-like phenotype. Our results identify NF-B signalling in the gut epithelium as a critical regulator of epithelial integrity and intestinal immune homeostasis, and have important implications for understanding the mechanisms controlling the pathogenesis of human inflammatory bowel disease.
