败血症
活性氧
激活转录因子
免疫学
ATF3
生物
促炎细胞因子
转录因子
微生物学
炎症
细胞生物学
基因表达
生物化学
发起人
基因
作者
Wolfram Hoetzenecker,Bernd Echtenacher,Emmanuella Guenova,Konrad Höetzenecker,Florian Woelbing,Jürgen Brück,Anna Teske,Nadejda Valtcheva,Kerstin Fuchs,Manfred Kneilling,Jihyeon Park,Kyu-Han Kim,Kyu‐Won Kim,Petra Hoffmann,Claus G. Krenn,Tsonwin Hai,Kamran Ghoreschi,Tilo Biedermann,Martin Röcken
出处
期刊:Nature Medicine
[Springer Nature]
日期:2011-12-18
卷期号:18 (1): 128-134
被引量:174
摘要
Sepsis, sepsis-induced hyperinflammation and subsequent sepsis-associated immunosuppression (SAIS) are important causes of death. Here we show in humans that the loss of the major reactive oxygen species (ROS) scavenger, glutathione (GSH), during SAIS directly correlates with an increase in the expression of activating transcription factor 3 (ATF3). In endotoxin-stimulated monocytes, ROS stress strongly superinduced NF-E2-related factor 2 (NRF2)-dependent ATF3. In vivo, this ROS-mediated superinduction of ATF3 protected against endotoxic shock by inhibiting innate cytokines, as Atf3(-/-) mice remained susceptible to endotoxic shock even under conditions of ROS stress. Although it protected against endotoxic shock, this ROS-mediated superinduction of ATF3 caused high susceptibility to bacterial and fungal infections through the suppression of interleukin 6 (IL-6). As a result, Atf3(-/-) mice were protected against bacterial and fungal infections, even under conditions of ROS stress, whereas Atf3(-/-)Il6(-/-) mice were highly susceptible to these infections. Moreover, in a model of SAIS, secondary infections caused considerably less mortality in Atf3(-/-) mice than in wild-type mice, indicating that ROS-induced ATF3 crucially determines susceptibility to secondary infections during SAIS.
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