Peroxisome proliferator-activated receptor gamma contributes to T lymphocyte apoptosis during sepsis.
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 gamma (PPARgamma) in provoking apoptosis in activated T lymphocytes. Therefore, we studied whether expression/activation of PPARgamma might contribute to T cell death during sepsis. We observed PPARgamma up-regulation in T cells of septic patients. In contrast to controls, PPARgamma expressing cells from septic patients responded with apoptosis when exposed to PPARgamma agonists. Cell demise was attenuated by SR-202, a synthetic PPARgamma antagonist, and specificity was further verified by excluding a proapoptotic response to a PPARalpha agonist. We propose that up-regulation of PPARgamma sensitizes T cells of septic patients to undergo apoptosis. PPARgamma activation in T cells requires an exogenous PPARgamma 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 PPARgamma plays a significant role in T cell apoptosis, contributing to lymphocyte loss in sepsis. Thus, inhibition of PPARgamma may turn out to be beneficial for patients suffering from lymphopenia during sepsis.
Soller
Mathias
M
Department of Biochemistry I, University Hospital, Johann Wolfgang Goethe-University Frankfurt, Germany.
Tautenhahn
Anja
A
Brüne
Bernhard
B
Zacharowski
Kai
K
John
Stefan
S
Link
Hartmut
H
von Knethen
Andreas
A
D017209:Apoptosis / Q000276:immunology*; D002478:Cells, Cultured; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008231:Lymphopenia / Q000097:blood / Q000276:immunology / Q000473:pathology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology*; D018805:Sepsis / Q000097:blood / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*
D009943:Organophosphorus Compounds; D047495:PPAR gamma; C051602:mifobate