炎癥性腸炎,，比如大腸潰瘍炎癥,，嚴(yán)重影響了全世界超過(guò)400萬(wàn)人的生活,，而有效的治療這些疾病需要從分子機(jī)理研究入手,。最近,，來(lái)自德國(guó)科隆大學(xué)和美因茲大學(xué)的研究人員，在意大利的歐洲分子生物學(xué)實(shí)驗(yàn)室,，破譯了引發(fā)慢性腸道炎癥的分子學(xué)密碼,。這項(xiàng)研究已經(jīng)發(fā)表在最近的《自然》雜志網(wǎng)絡(luò)版，揭示了一個(gè)在老鼠身上測(cè)試的單獨(dú)分子引發(fā)腸道炎癥的一些分子機(jī)理,，它可以作為研究人類炎癥性腸病的基礎(chǔ),。
我們的內(nèi)臟可以看做大量細(xì)菌的家，它們與人類和平共處并且能夠幫助食物消化,，如果它們滲透過(guò)腸壁,，那么這些細(xì)菌可能會(huì)造成危害并且引發(fā)疾病。這就是為一些薄薄的,、連續(xù)性的細(xì)胞層（上皮細(xì)胞）連接在腸道的表面創(chuàng)造了一個(gè)壁壘,，防止細(xì)菌通過(guò)這個(gè)界限。這種機(jī)制控制上皮細(xì)胞的完整性并且保持身體健康,，但是尚未完全清楚其機(jī)理,。
來(lái)自科隆大學(xué)的墨西哥小組成員Arianna Nency以及美因茲大學(xué)的Christoph Becker研究了NF-kB的作用，該特征分子保住細(xì)胞壓力,。在對(duì)上皮細(xì)胞的研究中,，科學(xué)家建立了不會(huì)表達(dá)NEMO的老鼠模型，這是一種會(huì)與NF-kB發(fā)生反映的蛋白質(zhì),，存在于上皮細(xì)胞當(dāng)中,。結(jié)果，這些老鼠患上和人類非常類似的大腸炎,。仔細(xì)觀察這些老鼠發(fā)現(xiàn),，它們的上皮細(xì)胞被破壞了。NF-kB是細(xì)胞生存的信號(hào),，如果沒(méi)有它,，預(yù)示著細(xì)胞已經(jīng)死亡，這種現(xiàn)象已經(jīng)發(fā)生在老鼠的腸道上,，單個(gè)上皮細(xì)胞死亡會(huì)損害腸道內(nèi)層,。通過(guò)這個(gè)裂縫細(xì)菌會(huì)滲透至腸道，而與之相聯(lián)系的免疫系統(tǒng)是體內(nèi)最強(qiáng)大的免疫系統(tǒng),，它會(huì)對(duì)入侵者發(fā)出強(qiáng)烈的免疫信號(hào),，在與細(xì)菌進(jìn)行斗爭(zhēng)的過(guò)程中，我們的上皮細(xì)胞會(huì)分泌一種信號(hào)帶來(lái)發(fā)炎的癥狀,。這將是一種惡性循環(huán),，炎癥信號(hào)能夠到達(dá)上皮細(xì)胞,，而上皮細(xì)胞對(duì)于缺乏NF-kB非常敏感，缺乏它將導(dǎo)致死亡,，更多的上皮細(xì)胞死亡將構(gòu)成腸道表皮上更大的裂縫,，這將導(dǎo)致更多的細(xì)菌進(jìn)入，結(jié)果是免疫系統(tǒng)對(duì)此進(jìn)行持續(xù)不斷的免疫反應(yīng),，導(dǎo)致我們所知道的腸道炎癥疾病的發(fā)生,。
關(guān)于腸道上皮細(xì)胞NF-kB信號(hào)缺乏導(dǎo)致炎癥這一現(xiàn)象的研究，提供了一個(gè)新的炎癥性腸病發(fā)病機(jī)理,。因?yàn)槔鲜蟮拿庖呦到y(tǒng)和人類的很相似,，通過(guò)老鼠模型試驗(yàn)獲得的結(jié)果，為解決引發(fā)人類炎癥性腸病發(fā)病機(jī)理提供了一條嶄新的思路,。
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: [email protected]).
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.
