title: Peroxisome proliferator-activated receptor γ-induced T cell apoptosis reduces survival during polymicrobial sepsis.
abstract: BACKGROUND
  Despite intensive research, sepsis displays the most prevalent cause of death on intensive care units. The hallmark of sepsis is an overshooting T-cell death that reduces host defense mechanisms and that is associated with poor patient survival. Previous in vitro studies revealed that the expression of the transcription factor peroxisome proliferator-activated receptor (PPAR) γ was increased in isolated T cells of patients with sepsis.
  
  
  OBJECTIVE
  We determined the importance of targeting PPARγ for sepsis treatment and underlying molecular mechanisms for T-cell apoptosis in vivo.
  
  
  METHODS
  To mimic human systemic inflammation and septic conditions, we used a nonlethal endotoxemia and a lethal cecum ligation and puncture polymicrobial sepsis model.
  
  
  RESULTS
  PPARγ inhibition in T cells with either the PPARγ antagonist GW9662 or a newly generated T cell-specific PPARγ knockout (Tc-PPARγ(-/-)) mice provided a survival advantage during polymicrobial sepsis in mice, which correlated with abrogated T-cell depletion in both in vivo models. Pathway analysis revealed increased antiapoptotic IL-2 and Bcl-2 expression, and activated prosurvival PI3K/Akt signaling under PPARγ-deficient conditions. In line, neutralizing IL-2 in Tc-PPARγ(-/-) mice resulted in T-cell apoptosis and increased mortality.
  
  
  CONCLUSIONS
  Our results provide evidence for a pivotal involvement of PPARγ in T-cell depletion by activating two important apoptosis pathways, and subsequently provoking the breakdown of defense mechanisms during systemic inflammation and sepsis.
authors.affiliation: Institute of Biochemistry I, Faculty of Medicine, Intensive Care Medicine and Pain Therapy, University Hospital, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: Martina Victoria
authors.initials: MV
authors.lastname: Schmidt
authors.forename: Patrick
authors.initials: P
authors.lastname: Paulus
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Kuhn
authors.forename: Andreas
authors.initials: A
authors.lastname: Weigert
authors.forename: Virginie
authors.initials: V
authors.lastname: Morbitzer
authors.forename: Kai
authors.initials: K
authors.lastname: Zacharowski
authors.forename: Volkhard A J
authors.initials: VA
authors.lastname: Kempf
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
authors.forename: Andreas
authors.initials: A
authors.lastname: von Knethen
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D007376:Interleukin-2 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010538:Peritonitis / Q000276:immunology / Q000382:microbiology / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018805:Sepsis / Q000276:immunology / Q000382:microbiology / Q000401:mortality* / Q000503:physiopathology; D015398:Signal Transduction; D015996:Survival Rate; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D047495:PPAR gamma; D019253:Proto-Oncogene Proteins c-bcl-2; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human