Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis.
Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis.
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DOI：
10.1038/s41467-017-01236-6
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发表时间：
2017-10-24
影响因子：
16.6
通讯作者：
Distler JHW
中科院分区：
文献类型：
--
作者：
Chakraborty D;Šumová B;Mallano T;Chen CW;Distler A;Bergmann C;Ludolph I;Horch RE;Gelse K;Ramming A;Distler O;Schett G;Šenolt L;Distler JHW
信号转导和转录激活因子3(STAT3)是一种信号转导和转录激活子3(STAT3)，它被多种激酶磷酸化，其中一些与包括系统性硬化症(SSC)在内的纤维化疾病中成纤维细胞的异常激活有关。在这里，我们表明促纤维化信号汇聚在STAT3上，并且STAT3可能是组织纤维化的一个重要的分子检查点。在SSc中，STAT3信号以转化生长因子β依赖的方式过度激活。体外和体内的表达谱和功能研究表明，STAT3的激活是由JAK、SRC、c-ABL和JNK激酶共同作用介导的。STAT3基因缺失的成纤维细胞对转化生长因子β的促纤维化作用不太敏感。成纤维细胞特异性的STAT3基因敲除或其药理抑制，可改善实验性小鼠的皮肤纤维化。因此，STAT3整合了几个促纤维化信号，可能是纤维化的核心介质。考虑到目前几种STAT3抑制剂正在进行临床试验，STAT3可能是SSc分子靶向治疗的候选药物。STAT3是一种转录因子，在系统性硬化症等纤维化疾病中被激活。在这里，作者表明，STAT3是多种促纤维化信号通路的汇合点，它的遗传消融或抑制可以改善小鼠模型的皮肤纤维化。
Signal transducer and activator of transcription 3 (STAT3) is phosphorylated by various kinases, several of which have been implicated in aberrant fibroblast activation in fibrotic diseases including systemic sclerosis (SSc). Here we show that profibrotic signals converge on STAT3 and that STAT3 may be an important molecular checkpoint for tissue fibrosis. STAT3 signaling is hyperactivated in SSc in a TGFβ-dependent manner. Expression profiling and functional studies in vitro and in vivo demonstrate that STAT3 activation is mediated by the combined action of JAK, SRC, c-ABL, and JNK kinases. STAT3-deficient fibroblasts are less sensitive to the pro-fibrotic effects of TGFβ. Fibroblast-specific knockout of STAT3, or its pharmacological inhibition, ameliorate skin fibrosis in experimental mouse models. STAT3 thus integrates several profibrotic signals and might be a core mediator of fibrosis. Considering that several STAT3 inhibitors are currently tested in clinical trials, STAT3 might be a candidate for molecular targeted therapies of SSc. STAT3 is a transcription factor that is activated in fibrotic diseases such as systemic sclerosis. Here the authors show that STAT3 is the converging point for multiple pro-fibrotic signalling pathways, and that its genetic ablation or inhibition ameliorate skin fibrosis in mouse models.
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影响因子：
3.8
作者：
Liu, Jia;Chen, Bailing;Chen, Fei
通讯作者：
Chen, Fei
DOI：
10.4161/jkst.22882
发表时间：
2013-01-01
期刊：
JAK-STAT
影响因子：
--
作者：
Fagard R;Metelev V;Souissi I;Baran-Marszak F
通讯作者：
Baran-Marszak F
影响因子：
6.5
作者：
Andres, Rosa M.;Carmen Montesinos, M.;Carmen Terencio, M.
通讯作者：
Carmen Terencio, M.
影响因子：
5.8
作者：
Kim, Ju-Hwa;Lee, Seok Chul;Yoon, Sungpil
通讯作者：
Yoon, Sungpil
DOI：
10.4049/jimmunol.1401779
发表时间：
2015-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Li C;Iness A;Yoon J;Grider JR;Murthy KS;Kellum JM;Kuemmerle JF
通讯作者：
Kuemmerle JF