T-cell-specific peroxisome proliferator-activated receptor gamma depletion inhibits T-cell apoptosis and improves survival of septic mice via an IL-2-dependent mechanism
- Introduction: Immune paralysis with massive T-cell apoptosis is a central pathogenic event during sepsis and correlates with septic patient mortality. Previous observations implied a crucial role of peroxisome proliferator-activated receptor gamma (PPARγ) during T-cell apoptosis. Methods: To elucidate mechanisms of PPARγ-induced T-cell depletion, we used an endotoxin model as well as the caecal ligation and puncture sepsis model to imitate septic conditions in wild-type versus conditional PPARγ knockout (KO) mice. Results: PPARγ KO mice showed a marked survival advantage compared with control mice. Their T cells were substantially protected against sepsis-induced death and showed a significantly higher expression of the pro-survival factor IL-2. Since PPARγ is described to repress nuclear factor of activated T cells (NFAT) transactivation and concomitant IL-2 expression, we propose inhibition of NFAT as the underlying mechanism allowing T-cell apoptosis. Corroborating our hypothesis, we observed up-regulation of the pro-apoptotic protein BIM and downregulation of the anti-apoptotic protein Bcl-2 in control mice, which are downstream effector proteins of IL-2 receptor signaling. Application of a neutralizing anti-IL-2 antibody reversed the pro-survival effect of PPARγ-deficient T cells and confirmed IL-2-dependent apoptosis during sepsis. Conclusion: Apparently antagonizing PPARγ in T cells might improve their survival during sepsis, which concomitantly enhances defence mechanisms and possibly provokes an increased survival of septic patients.
Author: | Martina V. Schmidt, Patrick Paulus, Anne-Marie Kuhn, Virginie Meilladec-Jullig, Kai ZacharowskiORCiDGND, Bernhard BrüneORCiD, Andreas von KnethenORCiDGND |
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URN: | urn:nbn:de:hebis:30-73049 |
DOI: | https://doi.org/10.1186/cc8093 |
ISSN: | 1466-609X |
ISSN: | 1364-8535 |
Parent Title (English): | Critical Care |
Publisher: | BioMed Central ; Springer |
Place of publication: | London ; Berlin ; Heidelberg |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2009/12/09 |
Date of first Publication: | 2009/11/11 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2009/12/09 |
Volume: | 13 |
Issue: | (Suppl 4):P37 |
Page Number: | 1 |
First Page: | 17 |
Last Page: | 17 |
Source: | Critical Care 2009, 13(Suppl 4):P37 ; doi:10.1186/cc8093 ; http://ccforum.com/content/13/S4/P37 |
HeBIS-PPN: | 220461228 |
Institutes: | Biochemie, Chemie und Pharmazie / Biochemie und Chemie |
Medizin / Medizin | |
Wissenschaftliche Zentren und koordinierte Programme / Sonderforschungsbereiche / Forschungskollegs | |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Licence (German): | Deutsches Urheberrecht |