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Critical Care

, 13:P37 | Cite as

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

  • MV Schmidt
  • P Paulus
  • A-M Kuhn
  • V Meilladec-Jullig
  • K Zacharowski
  • B Bruene
  • A von Knethen
Poster presentation
  • 743 Downloads

Keywords

Septic Patient Septic Mouse Downstream Effector Protein Immune Paralysis Caecal Ligation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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.

Copyright information

© BioMed Central Ltd 2009

Authors and Affiliations

  • MV Schmidt
    • 1
  • P Paulus
    • 2
  • A-M Kuhn
    • 1
  • V Meilladec-Jullig
    • 1
  • K Zacharowski
    • 2
  • B Bruene
    • 1
  • A von Knethen
    • 1
  1. 1.Institute of Biochemistry I,Goethe-University FrankfurtGermany
  2. 2.Department of Anaesthesia, Intensive Care Medicine &Pain Therapy, University Hospital FrankfurtGermany

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