Peroxisome proliferator-activated receptor γ (PPARγ) and sepsis

Abstract.

This review describes the role of the nuclear hormone receptor PPARγ as a double-edged sword in sepsis. On the one hand, PPARγ 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-α, or IL-1β, are repressed. Therefore, PPARγ is suggested to be beneficial in hyper-inflammatory diseases, such as sepsis. In animal models of sepsis, PPARγ agonist pretreatment auspiciously attenuated inflammation compared with control animals, accompanied by their improved survival rate. On the other hand, PPARγ 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 PPARγ is still ambiguous. Particularly its role in initiating apoptosis awaits further clarification to finally elucidate its impact on sepsis development.