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Hoetzenecker, Wolfram,Echtenacher, Bernd,Guenova, Emmanuella,Hoetzenecker, Konrad,Woelbing, Florian,Br체ck, J체rgen,Teske, Anna,Valtcheva, Nadejda,Fuchs, Kerstin,Kneilling, Manfred,Park, Ji-Hyeon,Kim, K Nature Publishing Group, a division of Macmillan P 2012 Nature medicine Vol.18 No.1
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<SUP>??/??</SUP> 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<SUP>??/??</SUP> mice were protected against bacterial and fungal infections, even under conditions of ROS stress, whereas Atf3<SUP>??/??</SUP>Il6<SUP>??/??</SUP> mice were highly susceptible to these infections. Moreover, in a model of SAIS, secondary infections caused considerably less mortality in Atf3<SUP>??/??</SUP> mice than in wild-type mice, indicating that ROS-induced ATF3 crucially determines susceptibility to secondary infections during SAIS.
Guenova, Emmanuella,Skabytska, Yuliya,Hoetzenecker, Wolfram,Weindl, Gü,nther,Sauer, Karin,Tham, Manuela,Kim, Kyu-Won,Park, Ji-Hyeon,Seo, Ji Hae,Ignatova, Desislava,Cozzio, Antonio,Levesque, Mitc National Academy of Sciences 2015 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.112 No.7
<P>Interleukin 4 (IL-4) can suppress delayed-type hypersensitivity reactions (DTHRs), including organ-specific autoimmune diseases in mice and humans. Despite the broadly documented antiinflammatory effect of IL-4, the underlying mode of action remains incompletely understood, as IL-4 also promotes IL-12 production by dendritic cells (DCs) and IFN-gamma-producing T(H)1 cells in vivo. Studying the impact of IL-4 on the polarization of human and mouse DCs, we found that IL-4 exerts opposing effects on the production of either IL-12 or IL-23. While promoting IL-12-producing capacity of DCs, IL-4 completely abrogates IL-23. Bone marrow chimeras proved that IL-4-mediated suppression of DTHRs relies on the signal transducer and activator of transcription 6 (STAT6)-dependent abrogation of IL-23 in antigen-presenting cells. Moreover, IL-4 therapy attenuated DTHRs by STAT6-and activating transcription factor 3 (ATF3)-dependent suppression of the IL-23/T(H)17 responses despite simultaneous enhancement of IL-12/T(H)1 responses. As IL-4 therapy also improves psoriasis in humans and suppresses IL-23/ T(H)17 responses without blocking IL-12/T(H)1, selective IL-4-mediated IL-23/T(H)17 silencing is promising as treatment against harmful inflammation, while sparing the IL-12-dependent T(H)1 responses.</P>