The immunobiology of colitis and cholangitis in interleukin-23p19 and interleukin-17A deleted dominant negative form of transforming growth factor beta receptor type II mice.
The immunobiology of colitis and cholangitis in interleukin-23p19 and interleukin-17A deleted dominant negative form of transforming growth factor beta receptor type II mice.
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DOI：
10.1002/hep.25803
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发表时间：
2012-10
期刊：
影响因子：
13.5
通讯作者：
Gershwin, M. Eric
中科院分区：
文献类型：
--
作者：
Ando, Yugo;Yang, Guo-Xiang;Tsuda, Masanobu;Kawata, Kazuhito;Zhang, Weici;Nakajima, Takahiko;Tsuneyama, Koichi;Leung, Patrick;Lian, Zhe-Xiong;Okazaki, Kazuichi;Ridgway, William M.;Norman, Gary L.;Ansari, Aftab A.;He, Xiao-Song;Coppel, Ross L.;Gershwin, M. Eric
dnTGFβRII小鼠在CD 4启动子的控制下表达显性阴性形式的TGFβ受体II，会发生自身免疫性结肠炎和胆管炎。我们先前观察到IL-12 p40的缺乏导致结肠和肝脏中炎症的显著减少。为了区分IL-12 p40介导的保护作用是否通过IL-12或IL-23途径发挥作用，我们产生了IL-23缺陷但IL-12不缺陷的IL-23 p19-/-dnTGFβRII菌株;对小鼠进行纵向随访，以了解疾病自然史和免疫反应的变化。有趣的是，IL-23 p19 −/−小鼠的结肠炎表现出显着改善，但胆道病理学没有变化;小鼠还表现出Th 17细胞群减少和IFN-γ水平不变。我们认为IL-12/Th 1通路在胆道疾病的发病机制中是必不可少的，而IL-23/Th 17通路介导结肠炎。为了进一步评估IL-23介导的结肠炎保护机制，我们产生了IL-17缺陷的IL-17 A −/− dnTGFβRII菌株，IL-17是IL-23依赖性Th 17细胞产生的主要效应细胞因子。IL-17 A基因的缺失不影响胆管炎或结肠炎的严重程度，表明IL-23/Th 17途径以IL-17非依赖性方式促成结肠疾病。这些结果证实，IL-12/Th 1通路对dnTGFβRII小鼠的胆道病理学至关重要，而结肠炎是由IL-23的直接作用引起的。
dnTGFβRII mice, expressing a dominant negative form of TGFβ receptor II under control of the CD4 promoter, develop autoimmune colitis and cholangitis . We previously observed that deficiency in IL-12p40 led to a marked diminution of inflammation in both the colon and the liver. To distinguish whether IL-12p40 mediated protection acted via the IL-12 or IL-23 pathways, we generated an IL-23p19−/− dnTGFβRII strain deficient in IL-23 but not in IL-12; mice were longitudinally followed for changes in the natural history of disease and immune responses. Interestingly, IL-23p19−/− mice demonstrate dramatic improvement in their colitis but no changes in biliary pathology; mice also manifest reduced Th17 cell populations and unchanged IFN-γ levels. We submit that the IL-12/Th1 pathway is essential for biliary disease pathogenesis, while the IL-23/Th17 pathway mediates colitis. To further assess the mechanism of the IL-23 mediated protection from colitis, we generated an IL-17A−/− dnTGFβRII strain deficient in IL-17, a major effector cytokine produced by IL-23-dependent Th17 cells. Deletion of the IL-17A gene did not affect the severity of either cholangitis or colitis, suggesting that the IL-23/Th17 pathway contributes to the colon disease in an IL-17-independent manner. These results affirm that the IL-12/Th1 pathway is critical to biliary pathology in dnTGFβRII mice while the colitis is caused by a direct effect of IL-23.
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影响因子：
4.4
作者：
Ghilardi, N;Kljavin, N;de Sauvage, FJ
通讯作者：
de Sauvage, FJ
影响因子：
32.4
作者：
Gorelik, L;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
4.6
作者：
Rong, G.;Zhou, Y.;Zhong, R.
通讯作者：
Zhong, R.
影响因子：
4.9
作者：
Carey, Rebecca;Jurickova, Ingrid;Denson, Lee A.
通讯作者：
Denson, Lee A.
影响因子：
12.8
作者：
Lan RY;Salunga TL;Tsuneyama K;Lian ZX;Yang GX;Hsu W;Moritoki Y;Ansari AA;Kemper C;Price J;Atkinson JP;Coppel RL;Gershwin ME
通讯作者：
Gershwin ME