The role of tuberous sclerosis complex 1 in regulating innate immunity.
The role of tuberous sclerosis complex 1 in regulating innate immunity.
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DOI：
10.4049/jimmunol.1102187
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发表时间：
2012-04-15
期刊：
影响因子：
--
通讯作者：
Zhong XP
中科院分区：
文献类型：
--
作者：
Pan H;O'Brien TF;Zhang P;Zhong XP
控制toll样受体诱导的反应包括内毒素耐受性的机制尚未得到很好的理解。结节性硬化症复合物1（TSC 1）是一种抑制哺乳动物雷帕霉素靶蛋白（mTOR）的肿瘤抑制因子。我们在这里表明，TSC 1的缺陷不仅导致mTOR复合物1（mTORC 1），而且JNK 1/2，在巨噬细胞中的脂多糖刺激后的增强激活。TSC 1缺陷型巨噬细胞产生升高的促炎细胞因子和一氧化氮响应于多种TLR配体。这种增强的TLR诱导的反应可以通过用化学抑制剂或小发夹RNA降低mTORC 1和JNK 1/2活性来抑制，这表明TSC 1通过mTORC 1和JNK 1/2负性控制TLR反应。TSC 1缺陷的影响似乎不限于TLR，因为NOD-和-RIG-I/MDA-5诱导的先天性应答在TSC 1缺陷的巨噬细胞中也改变。此外，TSC 1缺乏似乎会导致体外和体内内毒素耐受性诱导受损，这与JNK 1/2活化增加相关，并且可以通过JNK 1/2抑制来逆转。我们的研究结果揭示了TSC 1在调节先天免疫中的关键作用，通过负控制mTORC 1和JNK 1/2激活。
The mechanisms that control toll-like receptor induced responses including endotoxin tolerance have been not well understood. The tuberous sclerosis complex 1 (TSC1) is a tumor suppressor that inhibits the mammalian target of rapamycin (mTOR). We show here that deficiency of TSC1 results in enhanced activation of not only mTOR complex 1 (mTORC1), but also JNK1/2, following lipopolysaccharide stimulation in macrophages. TSC1 deficient macrophages produce elevated proinflammatory cytokines and nitric oxide in response to multiple TLR ligands. Such enhanced TLR-induced responses can be inhibited by reducing mTORC1 and JNK1/2 activities with chemical inhibitors or small hairpin RNA, suggesting that TSC1 negatively controls TLR responses through both mTORC1 and JNK1/2. The impact of TSC1 deficiency appeared not limited to TLRs, as NOD- and -RIG-I/MDA-5 induced innate responses were also altered in TSC1 deficient macrophages. Furthermore, TSC1 deficiency appears to cause impaired induction of endotoxin tolerance in vitro and in vivo, which is correlated with increased JNK1/2 activation and can be reversed by JNK1/2 inhibition. Our results reveal a critical role of TSC1 in regulating innate immunity by negative control of mTORC1 and JNK1/2 activation.
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影响因子：
20.3
作者：
Hackstein, H;Taner, T;Thomson, AW
通讯作者：
Thomson, AW
影响因子：
16.8
作者：
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通讯作者：
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影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.1084/jem.20081297
发表时间：
2008-09-29
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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通讯作者：
Zheng P
影响因子：
64.8
作者：
Colina, Rodney;Costa-Mattioli, Mauro;Sonenberg, Nahum
通讯作者：
Sonenberg, Nahum