Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice.
Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice.
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DOI：
10.1002/hep.25744
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发表时间：
2012-09
期刊：
影响因子：
13.5
通讯作者：
Gao, Bin
中科院分区：
文献类型：
--
作者：
Kong, Xiaoni;Feng, Dechun;Wang, Hua;Hong, Feng;Bertola, Adeline;Wang, Fu-Sheng;Gao, Bin
已知白细胞介素-22（IL-22）通过与受体IL-10 R2和IL-22 R1结合，在促进抗微生物免疫、炎症和屏障表面的组织修复中发挥关键作用。IL-22 R1通常被认为仅在上皮细胞中表达。在这项研究中，我们确定了高水平的IL-10 R2和IL-22 R1表达的肝星状细胞（HSC），主要的细胞类型参与肝纤维化，以应对肝损伤。在体外用IL-22处理诱导原代小鼠和人HSC中的信号转导子和转录激活子3（STAT 3）的激活。IL-22给药在体外和体内防止HSC凋亡，但令人惊讶的是，通过基因靶向（IL-22转基因小鼠）或外源性给予表达IL-22的腺病毒过表达IL-22减少了肝纤维化并加速了恢复期间肝纤维化的消退。此外，IL-22过表达或治疗增加了体内纤维化肝脏和体外培养的HSC中衰老相关β-半乳糖苷酶阳性HSC的数量，并降低了α-平滑肌肌动蛋白表达。STAT 3的缺失在体外阻止了IL-22诱导的HSC衰老，而组成性激活形式的STAT 3的过表达通过p53和p21依赖性途径促进HSC衰老。最后，IL-22处理上调HSC中细胞因子信号转导抑制因子3的表达。免疫沉淀分析显示，SOCS 3结合p53，随后增加p53及其靶基因的表达，有助于IL-22介导的HSC衰老。IL-22诱导表达IL-10 R2和IL-22 R1的HSC的衰老，从而改善肝纤维化。除了先前发现的IL-22的肝保护功能之外，IL-22的抗纤维化作用可能通过诱导HSC衰老来介导。
Interleukin-22 (IL-22) is known to play a key role in promoting antimicrobial immunity, inflammation, and tissue repair at barrier surfaces by binding to the receptors IL-10R2 and IL-22R1. IL-22R1 is generally thought to be expressed exclusively in epithelial cells. In this study, we identified high levels of IL-10R2 and IL-22R1 expression on hepatic stellate cells (HSCs), the predominant cell type involved in liver fibrogenesis in response to liver damage. In vitro treatment with IL-22 induced the activation of signal transducer and activator of transcription 3 (STAT3) in primary mouse and human HSCs. IL-22 administration prevented HSC apoptosis in vitro and in vivo, but surprisingly, the overexpression of IL-22 via either gene targeting (IL-22 transgenic mice) or exogenous administration of adenovirus expressing IL-22 reduced liver fibrosis and accelerated the resolution of liver fibrosis during recovery. Furthermore, IL-22 overexpression or treatment increased the number of senescence-associated β-galactosidase-positive HSCs and decreased α-smooth muscle actin expression in fibrotic livers in vivo and cultured HSCs in vitro. Deletion of STAT3 prevented IL-22-induced HSC senescence in vitro, whereas the overexpression of a constitutively activated form of STAT3 promoted HSC senescence via p53- and p21-dependent pathways. Finally, IL-22 treatment upregulated suppressor of cytokine signaling 3 expression in HSCs. Immunoprecipitation analyses revealed that SOCS3 bound p53 and subsequently increased the expression of p53 and its target genes, contributing to IL-22-mediated HSC senescence. IL-22 induces the senescence of HSCs, which express both IL-10R2 and IL-22R1, thereby ameliorating liver fibrogenesis. The anti-fibrotic effect of IL-22 is likely mediated via the induction of HSC senescence in addition to the previously discovered hepatoprotective functions of IL-22.
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影响因子：
7.8
作者：
Hampel, B;Wagner, M;Jansen-Dürr, P
通讯作者：
Jansen-Dürr, P
影响因子：
13.5
作者：
Schnabl, B;Purbeck, CA;Brenner, DA
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影响因子：
64.5
作者：
Kuilman, Thomas;Michaloglou, Chrysiis;Peeper, Daniel S.
通讯作者：
Peeper, Daniel S.
影响因子：
32.4
作者：
Zenewicz, Lauren A.;Yancopoulos, George D.;Flavell, Richard A.
通讯作者：
Flavell, Richard A.
影响因子：
5.3
作者：
Ferbeyre, G;de Stanchina, E;Lowe, SW
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Lowe, SW