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

J Leukoc Biol. 2006 Jan;79(1):235-43. doi: 10.1189/jlb.0205058.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / immunology*
  • Cells, Cultured
  • Humans
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Lymphopenia / blood
  • Lymphopenia / immunology
  • Lymphopenia / pathology
  • Organophosphorus Compounds / pharmacology
  • PPAR gamma / agonists
  • PPAR gamma / antagonists & inhibitors
  • PPAR gamma / blood
  • PPAR gamma / immunology*
  • Sepsis / blood
  • Sepsis / immunology*
  • Sepsis / pathology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology
  • Up-Regulation / drug effects
  • Up-Regulation / immunology*

Substances

  • Organophosphorus Compounds
  • PPAR gamma
  • mifobate