Peroxisome proliferator-activated receptor γ-induced T cell apoptosis reduces survival during polymicrobial sepsis. 2011

Martina Victoria Schmidt, and Patrick Paulus, and Anne-Marie Kuhn, and Andreas Weigert, and Virginie Morbitzer, and Kai Zacharowski, and Volkhard A J Kempf, and Bernhard Brüne, and Andreas von Knethen
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.

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.

UI MeSH Term Description Entries
D007376 Interleukin-2 A soluble substance elaborated by antigen- or mitogen-stimulated T-LYMPHOCYTES which induces DNA synthesis in naive lymphocytes. IL-2,Lymphocyte Mitogenic Factor,T-Cell Growth Factor,TCGF,IL2,Interleukin II,Interleukine 2,RU 49637,RU-49637,Ro-23-6019,Ro-236019,T-Cell Stimulating Factor,Thymocyte Stimulating Factor,Interleukin 2,Mitogenic Factor, Lymphocyte,RU49637,Ro 23 6019,Ro 236019,Ro236019,T Cell Growth Factor,T Cell Stimulating Factor
D010538 Peritonitis INFLAMMATION of the PERITONEUM lining the ABDOMINAL CAVITY as the result of infectious, autoimmune, or chemical processes. Primary peritonitis is due to infection of the PERITONEAL CAVITY via hematogenous or lymphatic spread and without intra-abdominal source. Secondary peritonitis arises from the ABDOMINAL CAVITY itself through RUPTURE or ABSCESS of intra-abdominal organs. Primary Peritonitis,Secondary Peritonitis,Peritonitis, Primary,Peritonitis, Secondary
D000813 Anilides Any aromatic amide obtained by acylation of aniline.
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013601 T-Lymphocytes Lymphocytes responsible for cell-mediated immunity. Two types have been identified - cytotoxic (T-LYMPHOCYTES, CYTOTOXIC) and helper T-lymphocytes (T-LYMPHOCYTES, HELPER-INDUCER). They are formed when lymphocytes circulate through the THYMUS GLAND and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T Cell,T Lymphocyte,T-Cells,Thymus-Dependent Lymphocytes,Cell, T,Cells, T,Lymphocyte, T,Lymphocyte, Thymus-Dependent,Lymphocytes, T,Lymphocytes, Thymus-Dependent,T Cells,T Lymphocytes,T-Cell,T-Lymphocyte,Thymus Dependent Lymphocytes,Thymus-Dependent Lymphocyte
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D015996 Survival Rate The proportion of survivors in a group, e.g., of patients, studied and followed over a period, or the proportion of persons in a specified group alive at the beginning of a time interval who survive to the end of the interval. It is often studied using life table methods. Cumulative Survival Rate,Mean Survival Time,Cumulative Survival Rates,Mean Survival Times,Rate, Cumulative Survival,Rate, Survival,Rates, Cumulative Survival,Rates, Survival,Survival Rate, Cumulative,Survival Rates,Survival Rates, Cumulative,Survival Time, Mean,Survival Times, Mean,Time, Mean Survival,Times, Mean Survival
D017209 Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, i.e., DNA FRAGMENTATION. It is genetically programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Apoptosis, Extrinsic Pathway,Apoptosis, Intrinsic Pathway,Caspase-Dependent Apoptosis,Classic Apoptosis,Classical Apoptosis,Programmed Cell Death,Programmed Cell Death, Type I,Apoptoses, Extrinsic Pathway,Apoptoses, Intrinsic Pathway,Apoptosis, Caspase-Dependent,Apoptosis, Classic,Apoptosis, Classical,Caspase Dependent Apoptosis,Cell Death, Programmed,Classic Apoptoses,Extrinsic Pathway Apoptoses,Extrinsic Pathway Apoptosis,Intrinsic Pathway Apoptoses,Intrinsic Pathway Apoptosis
D047495 PPAR gamma A nuclear transcription factor. Heterodimerization with RETINOID X RECEPTOR ALPHA is important in regulation of GLUCOSE metabolism and CELL GROWTH PROCESSES. It is a target of THIAZOLIDINEDIONES for control of DIABETES MELLITUS. PPARgamma,PPARgamma2,PPARgamma3,Peroxisome Proliferator-Activated Receptor gamma,Thiazolidinedione Receptor,mPPARgamma1,mPPARgamma2,Peroxisome Proliferator Activated Receptor gamma,Receptor, Thiazolidinedione
D050778 NFATC Transcription Factors A family of transcription factors characterized by the presence of highly conserved calcineurin- and DNA-binding domains. NFAT proteins are activated in the CYTOPLASM by the calcium-dependent phosphatase CALCINEURIN. They transduce calcium signals to the nucleus where they can interact with TRANSCRIPTION FACTOR AP-1 or NF-KAPPA B and initiate GENETIC TRANSCRIPTION of GENES involved in CELL DIFFERENTIATION and development. NFAT proteins stimulate T-CELL activation through the induction of IMMEDIATE-EARLY GENES such as INTERLEUKIN-2. NFAT Transcription Factor 1,NFAT Transcription Factor 2,NFAT Transcription Factor 3,NFAT Transcription Factor 4,NFAT Transcription Factor 5,Nuclear Factors of Activated T-Cells,NF-AT Proteins,NF-AT3 Protein,NF-AT4 Protein,NF-ATc1 Protein,NFAT Proteins,NFAT-1 Protein,NFAT-2 Protein,NFAT1 Protein,NFAT2 Protein,NFAT3 Protein,NFAT4 Protein,NFAT5 Protein,NFATC Proteins,NFATC1 Protein,NFATC1 Transcription Factor,NFATC2 Protein,NFATC2 Transcription Factor,NFATC3 Protein,NFATC3 Transcription Factor,NFATC4 Protein,NFATC4 Transcription Factor,NFATL1 Protein,NFATx Protein,NFATz Protein,Nuclear Factor of Activated T-Cells 5 Protein,Nuclear Factor of Activated T-Cells, Cytoplasmic,Nuclear Factor of Activated T-Cells, Cytoplasmic 1 Protein,Nuclear Factor of Activated T-Cells, Cytoplasmic 2 Protein,Nuclear Factor of Activated T-Cells, Cytoplasmic 3 Protein,Nuclear Factor of Activated T-Cells, Cytoplasmic 4 Protein,OREBP Protein,Osmotic Response Element Binding Protein,TonEBP Protein,Tonicity-Responsive Enhancer-Binding Protein,Transcription Factor NF-AT,Factor, NFATC1 Transcription,Factor, NFATC2 Transcription,Factor, NFATC3 Transcription,NF AT Proteins,NF AT3 Protein,NF AT4 Protein,NF ATc1 Protein,NF-AT, Transcription Factor,NFAT 1 Protein,NFAT 2 Protein,Nuclear Factor of Activated T Cells 5 Protein,Nuclear Factor of Activated T Cells, Cytoplasmic,Nuclear Factor of Activated T Cells, Cytoplasmic 1 Protein,Nuclear Factor of Activated T Cells, Cytoplasmic 2 Protein,Nuclear Factor of Activated T Cells, Cytoplasmic 3 Protein,Nuclear Factor of Activated T Cells, Cytoplasmic 4 Protein,Nuclear Factors of Activated T Cells,Tonicity Responsive Enhancer Binding Protein,Transcription Factor NF AT,Transcription Factor, NFATC1,Transcription Factor, NFATC2,Transcription Factor, NFATC3,Transcription Factor, NFATC4,Transcription Factors, NFATC

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