Targeted epithelial tight junction dysfunction causes immune activation and contributes to development of experimental colitis.
Targeted epithelial tight junction dysfunction causes immune activation and contributes to development of experimental colitis.
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DOI：
10.1053/j.gastro.2008.10.081
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发表时间：
2009-02
期刊：
影响因子：
29.4
通讯作者：
Turner JR
中科院分区：
文献类型：
--
作者：
Su L;Shen L;Clayburgh DR;Nalle SC;Sullivan EA;Meddings JB;Abraham C;Turner JR
炎症性肠病（IBD）是一种多因素疾病，被认为是由上皮功能、先天性和适应性免疫以及管腔微生物群的改变引起的。上皮屏障功能的具体作用仍不明确，但肠上皮肌球蛋白轻链激酶（MLCK）的活性增加，这是肿瘤坏死因子（TNF）诱导的屏障功能障碍的主要机制，发生在人IBD。我们的目的是确定是否在一个完整的上皮，原发性失调的肠上皮屏障的病理生理相关机制可以有助于结肠炎的发展。我们开发了转基因（Tg）小鼠，表达组成型活性MLCK（CA-MLCK），特别是在肠上皮细胞。评估其生理学、免疫状态和对疾病的易感性，并与非Tg同窝对照进行比较。CA-MLCK Tg小鼠表现出显著的屏障丧失，但正常生长和体重增加，未发生自发性疾病。然而，CA-MLCK Tg小鼠确实发生了粘膜免疫激活，表现为固有层CD 4+淋巴细胞数量增加、CD 11 c+细胞重新分布、干扰素（IFN）-γ和TNF产生增加以及上皮MHC I类表达增加。当用CD 4 + CD 45 + Rbhi淋巴细胞攻击时，Tg小鼠发展为加速和更严重形式的结肠炎，并且具有比非Tg同窝小鼠更短的存活时间。原发性病理生理相关的肠上皮屏障功能障碍不足以引起实验性肠道疾病，但可以广泛激活粘膜免疫反应，加速免疫介导的结肠炎的发作和严重程度。
Inflammatory bowel disease (IBD) is a multifactorial disease thought to be caused by alterations in epithelial function, innate and adaptive immunity, and luminal microbiota. The specific role of epithelial barrier function remains undefined, although increased activity of intestinal epithelial myosin light chain kinase (MLCK), which is the primary mechanism of tumor necrosis factor (TNF)-induced barrier dysfunction, occurs in human IBD. We aimed to determine whether in an intact epithelium, primary dysregulation of the intestinal epithelial barrier by pathophysiologically relevant mechanisms can contribute to development of colitis. We developed transgenic (Tg) mice that express constitutively-active MLCK (CA-MLCK) specifically within intestinal epithelia. Their physiology, immune status, and susceptibility to disease were assessed and compared to non-Tg littermate controls. CA-MLCK Tg mice demonstrated significant barrier loss, but grew and gained weight normally and did not develop spontaneous disease. CA-MLCK Tg mice did, however, develop mucosal immune activation demonstrated by increased numbers of lamina propria CD4+ lymphocytes, redistribution of CD11c+ cells, increased production of interferon (IFN)-γ and TNF, as well as increased expression of epithelial MHC class I. When challenged with CD4+CD45+ Rbhi lymphocytes, Tg mice developed an accelerated and more severe form of colitis and had shorter survival times than non-Tg littermates. Primary pathophysiologically relevant intestinal epithelial barrier dysfunction is insufficient to cause experimental intestinal disease but can broadly activate mucosal immune responses and accelerate the onset and severity of immune-mediated colitis.
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DOI：
10.1084/jem.20050407
发表时间：
2006-03-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Olson TS;Reuter BK;Scott KG;Morris MA;Wang XM;Hancock LN;Burcin TL;Cohn SM;Ernst PB;Cominelli F;Meddings JB;Ley K;Pizarro TT
通讯作者：
Pizarro TT
DOI：
10.1111/j.1440-1746.2008.05325.x
发表时间：
2008-05-01
影响因子：
4.1
作者：
Pulimood, Anna B.;Ramakrishna, Balakrishna S.;Balasubramanian, Kunnissery A.
通讯作者：
Balasubramanian, Kunnissery A.
影响因子：
29.4
作者：
KATZ, KD;HOLLANDER, D;ROTTER, JI
通讯作者：
ROTTER, JI
DOI：
10.1083/jcb.129.2.489
发表时间：
1995-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hermiston ML;Gordon JI
通讯作者：
Gordon JI
影响因子：
4.4
作者：
Marski, M;Kandula, S;Abraham, C
通讯作者：
Abraham, C