發(fā)炎性腸道疾?。╥nflammatory bowel disease, IBD）主要是指克隆氏癥（Crohn's disease, CD）及潰瘍性結(jié)腸炎（ulcerative colitis, UC）兩種疾病,，臨床上的特點是容易復發(fā)，并形成慢性以及無法預(yù)期的病程,。全世界約有四百萬人受到這種疾病的影響,。
研究人員希望可以發(fā)展出有效的療法，但是必需要先了解這種疾病底下的分子機制,。德國科隆和美因法大學和位于意大利的歐洲分子生物學實驗室的小鼠生物學單位(EMBL)的研究人員,，解開了引起慢性發(fā)炎性腸道疾病的分子信號。這項研究發(fā)表于這一期的Nature網(wǎng)絡(luò)版中。研究結(jié)果證實,，阻攔這種信號分子會造成小鼠嚴重的腸道發(fā)炎,，這可能是人類發(fā)炎性腸道疾病的分子機制。
研究人員調(diào)查NF kb如何幫助腸道上皮細胞應(yīng)付壓力,。他們利用遺傳技術(shù),，產(chǎn)生不表現(xiàn)NEMO 的一個小鼠模型，這種蛋白質(zhì)對于活化小腸上皮細胞NF kb是非常重要的,。結(jié)果,，這些小鼠發(fā)生與人類發(fā)炎性腸道疾病非常相似的慢性腸道炎癥。因此研究人員認為,，腸道上皮的NF kb信號途徑發(fā)生缺陷,，可能是導致發(fā)炎性腸道疾病的原因。
(資料來源 : Bio.com)
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: [email protected]).
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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.
