Peroxisome Proliferator-Activated Receptor δ Regulates Inflammation via NF-κB Signaling in Polymicrobial Sepsis

The nuclear peroxisome proliferator-activated receptor delta (PPAR delta) is an important regulator of lipid metabolism. In contrast to its known effects on energy homeostasis, its biological role on inflammation is not well understood. We investigated the role of PPAR delta in the modulation of the nuclear factor-kappa B (NF-kappa B)-driven inflammatory response to polytnicrobial sepsis in vivo and in macrophages in vitro. We demonstrated that administration of GW0742, a specific PPAR delta ligand, provided beneficial effects to rats subjected to cecal ligation and puncture, as shown by reduced systemic release of pro-inflammatory cytokines and neutrophil infiltration in lung, liver, and cecum, when compared with vehicle treatment. Molecular analysis revealed that treatment with GW0742 reduced NF-kappa B binding to DNA in lung and liver. In parallel experiments, heterozygous PPAR delta-deficient mice suffered exaggerated lethality when subjected to cecal ligation and puncture and exhibited severe lung injury and higher levels of circulating tumor necrosis factor-alpha (TNF alpha) and keratinocyte-derived chemokine than wild-type mice. Furthermore, in lipopolysaccharide-stimulated J774.A1 macrophages, 6W0742 reduced TNF alpha production by inhibiting NF-kappa B activation. RNA silencing of PPAR delta abrogated the inhibitory effects of GW0742 on TNF alpha production. Chromatin inununoprecipitation assays revealed that PPAR delta displaced the NF-kappa B p65 subunit from the kappa B elements of the TNF alpha promoter, while recruiting the co-repressor BCL6. These data suggest that PPAR delta is a crucial antiinflammatory regulator, providing a basis for novel sepsis therapies. (Am J Pathol 2010, 177:1834-1847; DOI: 10.2353/ajpath.2010.091010)