| First Author | Zingarelli B | Year | 2010 |
| Journal | Am J Pathol | Volume | 177 |
| Issue | 4 | Pages | 1834-47 |
| PubMed ID | 20709805 | Mgi Jnum | J:165344 |
| Mgi Id | MGI:4837034 | Doi | 10.2353/ajpath.2010.091010 |
| Citation | Zingarelli B, et al. (2010) Peroxisome proliferator-activated receptor {delta} regulates inflammation via NF-{kappa}B signaling in polymicrobial sepsis. Am J Pathol 177(4):1834-47 |
| abstractText | The nuclear peroxisome proliferator-activated receptor delta (PPARdelta) 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 PPARdelta in the modulation of the nuclear factor-kappaB (NF-kappaB)-driven inflammatory response to polymicrobial sepsis in vivo and in macrophages in vitro. We demonstrated that administration of GW0742, a specific PPARdelta 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-kappaB binding to DNA in lung and liver. In parallel experiments, heterozygous PPARdelta-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 (TNFalpha) and keratinocyte-derived chemokine than wild-type mice. Furthermore, in lipopolysaccharide-stimulated J774.A1 macrophages, GW0742 reduced TNFalpha production by inhibiting NF-kappaB activation. RNA silencing of PPARdelta abrogated the inhibitory effects of GW0742 on TNFalpha production. Chromatin immunoprecipitation assays revealed that PPARdelta displaced the NF-kappaB p65 subunit from the kappaB elements of the TNFalpha promoter, while recruiting the co-repressor BCL6. These data suggest that PPARdelta is a crucial anti-inflammatory regulator, providing a basis for novel sepsis therapies. |
