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

Poster presentation: from Sepsis 2009 Amsterdam, The Netherlands. 11-14 November 2009 Introduction Immune paralysis with massive T-cell apoptosis is a central pathogenic event during sepsis and correlates with septic pat
Poster presentation: from Sepsis 2009 Amsterdam, The Netherlands. 11-14 November 2009 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 (PPARgamma) during T-cell apoptosis. Methods To elucidate mechanisms of PPARgamma-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 PPARgamma knockout (KO) mice. Results PPARgamma 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 PPARgamma 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 PPARgamma-deficient T cells and confirmed IL-2-dependent apoptosis during sepsis. Conclusion Apparently antagonizing PPARgamma 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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Metadaten
Author:Martina V. Schmidt, Patrick Paulus, Anne-Marie Kuhn, Virginie Meilladec-Jullig, Kai Zacharowski, Bernhard Brüne, Andreas von Knethen
URN:urn:nbn:de:hebis:30-73049
Document Type:Article
Language:English
Date of Publication (online):2009/12/09
Year of first Publication:2009
Publishing Institution:Univ.-Bibliothek Frankfurt am Main
Release Date:2009/12/09
Source:Critical Care 2009, 13(Suppl 4):P37 ; doi:10.1186/cc8093 ; http://ccforum.com/content/13/S4/P37
HeBIS PPN:220461228
Institutes:Biochemie und Chemie
Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License Logo Veröffentlichungsvertrag für Publikationen

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