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) γ was increased in isolated T cells of patients with sepsis. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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.
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) γ was increased in isolated T cells of patients with sepsis. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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: Ana Elisa Ferreira; Flavia Sisti; Fabiane Sônego; Suojuan Wang; Luciano Ribeiro Filgueiras; Stephanie Brandt; Ana Paula Moreira Serezani; Hong Du; Fernando Q Cunha; Jose Carlos Alves-Filho; Carlos Henrique Serezani Journal: J Immunol Date: 2014-01-31 Impact factor: 5.422
Authors: Andreas von Knethen; Lisa Katharina Sha; Tilo Knape; Laura Kuchler; Annika Klara Giegerich; Martin Schulz; Ingeborg A Hauser; Bernhard Brüne Journal: J Mol Med (Berl) Date: 2015-01-06 Impact factor: 4.599
Authors: William J Housley; Catherine O Adams; Amanda G Vang; Stefan Brocke; Frank C Nichols; Melissa LaCombe; Thiruchandurai V Rajan; Robert B Clark Journal: J Immunol Date: 2011-09-09 Impact factor: 5.422