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(Journal of Leukocyte Biology. 2006;79:235-243.)
© 2006 by Society for Leukocyte Biology

Peroxisome proliferator-activated receptor contributes to T lymphocyte apoptosis during sepsis

Mathias Soller^*, Anja Tautenhahn^*, Bernhard Brüne^*, Kai Zacharowski, Stefan John, Hartmut Link and Andreas von Knethen^*,1

^* Department of Biochemistry I, University Hospital, Johann Wolfgang Goethe-University Frankfurt, Germany;
Department of Anesthesiology, Molecular Cardioprotection and Inflammation Group, Faculty of Medicine, University of Düsseldorf, Germany;
Department of Medicine IV-Experimental Division, Faculty of Medicine, University of Erlangen-Nürnberg, Erlangen, Germany; and
Westpfalz-Klinikum Kaiserslautern, Department of Internal Medicine I, Germany

¹ Correspondence: Department of Biochemistry I, University Hospital, Johann Wolfgang Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. E-mail: v_knethen{at}zbc.kgu.de

In the last two decades, extensive research failed to significantly improve the outcome of patients with sepsis. In part, this drawback is based on a gap in our knowledge about molecular mechanisms understanding the pathogenesis of sepsis. During sepsis, T cells are usually depleted. Recent studies in mice and human cells suggested a role of the peroxisome proliferator-activated receptor (PPAR) in provoking apoptosis in activated T lymphocytes. Therefore, we studied whether expression/activation of PPAR might contribute to T cell death during sepsis. We observed PPAR up-regulation in T cells of septic patients. In contrast to controls, PPAR expressing cells from septic patients responded with apoptosis when exposed to PPAR agonists. Cell demise was attenuated by SR-202, a synthetic PPAR antagonist, and specificity was further verified by excluding a proapoptotic response to a PPAR agonist. We propose that up-regulation of PPAR sensitizes T cells of septic patients to undergo apoptosis. PPAR activation in T cells requires an exogenous PPAR agonist, which we identified in sera of septic patients. Septic sera were used to study reporter gene expression containing a PPAR-responsive element. We conclude that PPAR plays a significant role in T cell apoptosis, contributing to lymphocyte loss in sepsis. Thus, inhibition of PPAR may turn out to be beneficial for patients suffering from lymphopenia during sepsis.

Key Words: cell death • bacterial • inflammation • leukopenia

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