Recently, we provided evidence that PKCα depletion in monocytes/macrophages contributes to cellular desensitization during sepsis. We demonstrate that peroxisome proliferator–activated receptor γ (PPARγ) agonists dose dependently block PKCα depletion in response to the diacylglycerol homologue PMA in RAW 264.7 and human monocyte–derived macrophages. In these cells, we observed PPARγ-dependent inhibition of nuclear factor-κB (NF-κB) activation and TNF-α expression in response to PMA. Elucidating the underlying mechanism, we found PPARγ1 expression not only in the nucleus but also in the cytoplasm. Activation of PPARγ1 wild type, but not an agonist-binding mutant of PPARγ1, attenuated PMA-mediated PKCα cytosol to membrane translocation. Coimmunoprecipitation assays pointed to a protein–protein interaction of PKCα and PPARγ1, which was further substantiated using a mammalian two-hybrid system. Applying PPARγ1 mutation and deletion constructs, we identified the hinge helix 1 domain of PPARγ1 that is responsible for PKCα binding. Therefore, we conclude that PPARγ1-dependent inhibition of PKCα translocation implies a new model of macrophage desensitization.

This review describes the role of the nuclear hormone receptor PPARgamma as a double-edged sword in sepsis. On the one hand, PPARgamma inhibits pro-inflammatory gene expression, predominantly by scavenging transcription factors and their cofactors, thus preventing them from binding to their cognate binding sites in the promoters of target genes. The expressions of the affected genes, such as those for inducible nitric oxide synthase, TNF-alpha, or IL-1beta, are repressed. Therefore, PPARgamma is suggested to be beneficial in hyper-inflammatory diseases, such as sepsis. In animal models of sepsis, PPARgamma agonist pretreatment auspiciously attenuated inflammation compared with control animals, accompanied by their improved survival rate. On the other hand, PPARgamma provokes apoptosis, which in the hyper-inflammatory phase of sepsis might be helpful because the number of immune cells, such as monocytes, macrophages, and neutrophils, involved in secreting high amounts of proinflammatory mediators will be reduced. In contrast, during the anti-inflammatory phase, cell death of immune cells, especially of T lymphocytes, is supposed to be deleterious. Under these circumstances, a second infection cannot be adequately answered, thus causing septic shock and multi-organ dysfunction syndrome. Therefore the role of PPARgamma is still ambiguous. Particularly its role in initiating apoptosis awaits further clarification to finally elucidate its impact on sepsis development.

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.

Thiazolidinediones are synthetic agonists for the transcription factor peroxisome proliferator-activated receptor ␥ (PPAR␥) and are therapeutically used as insulin sensitizers. Besides therapeutical benefits, potential side effects such as the induction of cell death by thiazolidinediones deserve consideration. Although PPAR␥-dependent and -independent cell death in response to thiazolidinediones has been described, we provide evidence supporting a new mechanism to account for thiazolidinedione-initiated but PPAR␥-independent cell demise. In Jurkat T cells, ciglitazone and troglitazone provoked rapid and dose-dependent cell death, whereas rosiglitazone did not alter cell viability. We found induction of apoptosis by troglitazone, whereas ciglitazone caused necrosis. Because preincubation with the reactive oxygen species (ROS) scavengers manganese (III) tetrakis(4-benzoic acid) porphyrin and vitamin C significantly inhibited ciglitazone-and partially troglitazone-mediated cell death, we suggest that ROS contribute to cytotoxicity. Assuming that ROS originate from mitochondria, studies in submitochondrial particles demonstrated that all thiazolidinediones inhibited complex I of the mitochondrial respiratory chain. However, only ciglitazone and troglitazone lowered complex II activity as well. Pharmacological inhibition of complexes I and II documented that complex II inhibition in Jurkat cells caused massive apoptotic cell death, whereas inhibition of complex I provoked only marginally apoptosis after 4-h treatment. Therefore, inhibition of complex II by ciglitazone and troglitazone is the main trigger of cell death. ATP depletion by ciglitazone, in contrast to troglitazone, is responsible for induction of necrosis. Our results demonstrate that despite their similar molecular structure, thiazolidinediones differently affect cell death, which might help to explain some adverse effects occurring during thiazolidinedione-based therapies.

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