Hoetzenecker, Wolfram and Echtenacher, Bernd and Guenova, Emmanuella and Hoetzenecker, Konrad and Woelbing, Florian and Brueck, Juergen and Teske, Anna and Valtcheva, Nadejda and Fuchs, Kerstin and Kneilling, Manfred and Park, Ji-Hyeon and Kim, Kyu-Han and Kim, Kyu-Won and Hoffmann, Petra and Krenn, Claus and Hai, Tsonwin and Ghoreschi, Kamran and Biederman, Tilo and Roecken, Martin (2012) ROS-induced ATF3 causes susceptibility to secondary infections during sepsis-associated immunosuppression. NATURE MEDICINE, 18 (1). pp. 128-134. ISSN 1078-8956, 1546-170X
Full text not available from this repository. (Request a copy)Abstract
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(-/-)ll6(-/-) 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACTIVATING TRANSCRIPTION FACTOR-3; OXIDATIVE STRESS; MONOCLONAL-ANTIBODY; NEGATIVE REGULATOR; GENETIC-CONTROL; PROTECTS MICE; SEPTIC SHOCK; DOUBLE-BLIND; GLUTATHIONE; INFLAMMATION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Immunologie Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 25 May 2020 10:15 |
| Last Modified: | 25 May 2020 10:15 |
| URI: | https://pred.uni-regensburg.de/id/eprint/19592 |
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