Enterocyte-derived TAK1 signaling prevents epithelium apoptosis and the development of ileitis and colitis.
Enterocyte-derived TAK1 signaling prevents epithelium apoptosis and the development of ileitis and colitis.
复制标题
肠细胞衍生的 TAK1 信号传导可防止上皮细胞凋亡以及回肠炎和结肠炎的发展。
DOI：
10.4049/jimmunol.181.2.1143
复制
发表时间：
2008-07-15
期刊：
影响因子：
--
通讯作者：
Ninomiya-Tsuji J
中科院分区：
文献类型：
--
作者：
Kajino-Sakamoto R;Inagaki M;Lippert E;Akira S;Robine S;Matsumoto K;Jobin C;Ninomiya-Tsuji J
最近的研究表明，TAK 1激酶是几种先天免疫信号通路的重要中间体。在这项研究中，我们研究了TAK 1信号在维持肠道内稳态的作用，通过产生肠细胞特异性组成型和诱导型基因缺失TAK 1小鼠。我们发现，肠细胞特异性组成型TAK 1缺失小鼠自发地发生肠道炎症，如通过组织学分析观察到的，并且在出生时增强了IL-1β、MIP 2和IL-6的表达，这伴随着显著的肠细胞凋亡。当使用诱导型敲除系统在4周龄小鼠的肠上皮中缺失TAK 1时，肠细胞在基因缺失开始后的2-3天内经历细胞凋亡并且发生肠道炎症。我们发现，当肠细胞特异性组成型TAK 1缺失小鼠与TNF受体1（TNFR 1）−/−小鼠杂交时，肠细胞凋亡和肠道炎症强烈减弱。然而，这些小鼠后来（>14天）发展回肠炎和结肠炎。因此，肠上皮细胞中的TAK 1信号传导对于防止TNF依赖性上皮细胞凋亡和TNF非依赖性回肠炎和结肠炎的发展是必不可少的。我们认为TAK 1信号的异常可能会破坏肠道内稳态，并促进炎症性疾病的发展。
Recent studies have revealed that TAK1 kinase is an essential intermediate in several innate immune signaling pathways. In this study, we investigated the role of TAK1 signaling in maintaining intestinal homeostasis by generating enterocytes-specific constitutive and inducible gene deleted TAK1 mice. We found that enterocyte-specific constitutive TAK1 deleted mice spontaneously developed intestinal inflammation as observed by histological analysis and enhanced expression of IL-1β, MIP2 and IL-6 around the time of birth, which was accompanied by significant enterocytes apoptosis. When TAK1 was deleted in the intestinal epithelium of 4-week-old mice using an inducible knockout system, enterocytes underwent apoptosis and intestinal inflammation developed within 2–3 days following the initiation of gene deletion. We found that enterocytes apoptosis and intestinal inflammation were strongly attenuated when enterocyte-specific constitutive TAK1 deleted mice were crossed to TNF receptor 1 (TNFR1)−/− mice. However, these mice later (>14 days) developed ileitis and colitis. Thus, TAK1 signaling in enterocytes is essential for preventing TNF-dependent epithelium apoptosis and the TNF-independent development of ileitis and colitis. We propose that aberration in TAK1 signaling might disrupt intestinal homeostasis and favor the development of inflammatory disease.
登录
查看更多内容
DOI：
10.1073/pnas.1432897100
发表时间：
2003-07-08
影响因子：
11.1
作者：
Marini, M;Bamias, G;Cominelli, F
通讯作者：
Cominelli, F
影响因子：
64.8
作者：
Ishitani, T;Ninomiya-Tsuji, J;Matsumoto, K
通讯作者：
Matsumoto, K
影响因子：
4.8
作者：
Kim, Jae-Young;Omori, Emily;Ninomiya-Tsuji, Jun
通讯作者：
Ninomiya-Tsuji, Jun
DOI：
10.1073/pnas.0603089103
发表时间：
2006-08-01
影响因子：
11.1
作者：
Liu, Hong-Hsing;Xie, Min;Chen, Zhijian J.
通讯作者：
Chen, Zhijian J.
影响因子：
4.6
作者：
Jadrich, JL;O'Connor, MB;Coucouvanis, E
通讯作者：
Coucouvanis, E