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.

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Author:Martina V. Schmidt, Patrick Paulus, Anne-Marie Kuhn, Virginie Meilladec-Jullig, Kai ZacharowskiORCiDGND, Bernhard BrüneORCiD, Andreas von KnethenORCiDGND
Parent Title (English):Critical Care
Publisher:BioMed Central ; Springer
Place of publication:London ; Berlin ; Heidelberg
Document Type:Article
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
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
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):License LogoDeutsches Urheberrecht