Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice.
Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice.
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DOI：
10.1053/j.gastro.2012.05.049
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发表时间：
2012-09
期刊：
影响因子：
29.4
通讯作者：
Kisseleva T
中科院分区：
文献类型：
--
作者：
Meng F;Wang K;Aoyama T;Grivennikov SI;Paik Y;Scholten D;Cong M;Iwaisako K;Liu X;Zhang M;Österreicher CH;Stickel F;Ley K;Brenner DA;Kisseleva T
IL-17信号传导与肺和皮肤纤维化有关。在这里，我们研究了IL-17信号转导在肝纤维化发病机制中的作用。使用胆汁淤积性和肝毒性肝损伤模型，将野生型小鼠的肝纤维化发展与IL-17 RA −/−小鼠、免疫细胞和枯否细胞中缺乏IL-17信号传导的骨髓嵌合小鼠（IL-17 RA −/−→wt和IL-17 A −/− →wt小鼠）或肝脏驻留细胞（Wt→ IL-17 RA −/−小鼠）进行比较。我们确定IL-17 A及其受体在肝损伤中高度诱导，并且对炎症细胞和肝驻留细胞都具有强烈的促纤维化作用。IL-17信号传导促进炎症细胞产生IL-6、IL-1β和TNF-α，并增加TGF-β1（主要促纤维化细胞因子）的表达。IL-17通过激活Stat 3信号通路直接诱导肝星状细胞（HSC）中I型胶原蛋白的产生。HSC中缺乏Stat 3信号传导的小鼠（GFAPStat 3 −/−小鼠）对纤维化不太敏感。此外，免疫细胞中IL-23的缺失导致肝纤维化的减弱，而IL-22的缺失加剧纤维化。IL-22和IL-17 E（IL-25，IL-23的负调节因子）的给药可保护小鼠免受BDL诱导的肝纤维化。IL-17通过多种机制诱导肝纤维化，并可能作为抗纤维化治疗的有吸引力的靶点。
IL-17 signaling has been implicated in lung and skin fibrosis. Here we examined the role of IL-17 signaling in the pathogenesis of liver fibrosis. Using cholestatic and hepatotoxic models of liver injury, the development of liver fibrosis in wild type mice was compared to IL-17RA−/− mice, and to bone marrow chimeric mice devoid of IL-17 signaling in immune cells and Kupffer cells (IL-17RA−/−→wt and IL-17A−/− →wt mice), or in liver resident cells (Wt→ IL-17RA−/− mice). We determined that IL-17A and its receptor is highly induced in liver injury and has a strong pro-fibrogenic effect on both inflammatory and liver resident cells. IL-17 signaling facilitates production of IL-6, IL-1β, and TNF-α by inflammatory cells, and increases the expression of TGF-β1, the major pro-fibrogenic cytokine. IL-17 directly induces collagen Type I production in hepatic stellate cells (HSCs) via activation of the Stat3 signaling pathway. Mice devoid of Stat3 signaling in HSCs (GFAPStat3−/− mice) are less susceptible to fibrosis. Furthermore, deletion of IL-23 in immune cells results in attenuation of liver fibrosis, while deletion of IL-22 exacerbates fibrosis. Administration of IL-22 and IL-17E (IL-25, a negative regulator of IL-23) protects mice from BDL-induced liver fibrosis. IL-17 induces liver fibrosis through multiple mechanisms and may serve as an attractive target for anti-fibrotic therapy.
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影响因子：
32.4
作者：
Kang Z;Altuntas CZ;Gulen MF;Liu C;Giltiay N;Qin H;Liu L;Qian W;Ransohoff RM;Bergmann C;Stohlman S;Tuohy VK;Li X
通讯作者：
Li X
影响因子：
15.9
作者：
Kisseleva, Tatiana;Song, Li;Schindler, Christian
通讯作者：
Schindler, Christian
DOI：
10.1073/pnas.0611589104
发表时间：
2007-05-01
影响因子：
11.1
作者：
Maitra, Amarnath;Shen, Fang;Gaffen, Sarah L.
通讯作者：
Gaffen, Sarah L.
DOI：
10.1073/pnas.82.24.8681
发表时间：
1985-12-01
影响因子：
11.1
作者：
FRIEDMAN, SL;ROLL, FJ;BISSELL, DM
通讯作者：
BISSELL, DM
影响因子：
32.4
作者：
Takeda, K;Clausen, BE;Akira, S
通讯作者：
Akira, S