2011 Jul 1 - Peroxisome Proliferator–activated Receptor –induced T Cell Apoptosis Reduces Survival during Polymicrobial Sepsis
- Category: Am J of Respiratory & Critical Care Medicine
- Last Updated on Wednesday, 03 April 2013 01:12
Rationale: 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) was increased in isolated T cells of patients with sepsis.
Objectives: We determined the importance of targeting PPAR 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.
Measurements and Main Results: PPAR inhibition in T cells with either the PPAR antagonist GW9662 or a newly generated T cell–specific PPAR knockout (Tc-PPAR–/–) 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 PPAR-deficient conditions. In line, neutralizing IL-2 in Tc-PPAR–/– mice resulted in T-cell apoptosis and increased mortality.
Conclusions: Our results provide evidence for a pivotal involvement of PPAR in T-cell depletion by activating two important apoptosis pathways, and subsequently provoking the breakdown of defense mechanisms during systemic inflammation and sepsis.