Article

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

Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center and College of Medicine, University of Cincinnati, Cincinnati, Ohio 45229, USA.
American Journal Of Pathology (Impact Factor: 4.6). 10/2010; 177(4):1834-47. DOI: 10.2353/ajpath.2010.091010
Source: PubMed

ABSTRACT The nuclear peroxisome proliferator-activated receptor δ (PPARδ) 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 PPARδ in the modulation of the nuclear factor-κB (NF-κB)-driven inflammatory response to polymicrobial sepsis in vivo and in macrophages in vitro. We demonstrated that administration of GW0742, a specific PPARδ 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-κB binding to DNA in lung and liver. In parallel experiments, heterozygous PPARδ-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-α (TNFα) and keratinocyte-derived chemokine than wild-type mice. Furthermore, in lipopolysaccharide-stimulated J774.A1 macrophages, GW0742 reduced TNFα production by inhibiting NF-κB activation. RNA silencing of PPARδ abrogated the inhibitory effects of GW0742 on TNFα production. Chromatin immunoprecipitation assays revealed that PPARδ displaced the NF-κB p65 subunit from the κB elements of the TNFα promoter, while recruiting the co-repressor BCL6. These data suggest that PPARδ is a crucial anti-inflammatory regulator, providing a basis for novel sepsis therapies.

Download full-text

Full-text

Available from: James A Cook, Jul 17, 2015
0 Followers
 · 
115 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In examining the liver's response to sepsis, our laboratory has found that septic hepatocytes exhibit a higher degree of necrosis when compared with septic thymocytes, which typically die through the canonical apoptotic pathway. Recently, an adaptor protein associated with the Fas/TNF death receptor pathway, receptor interacting protein 1 (RIP1), has been shown to be critical for determining whether a cell's death is apoptotic or necrotic. We propose to test the central hypothesis that RIP1 activation by death receptor (Fas) during sepsis determines whether the hepatocytes' fate is apoptotic versus necrotic. We approached this problem by delivering RIP1 siRNA in vivo to C57BL/6 mice and observing changes in mortality after septic challenge. Contrary to our hypothesis, RIP1-silenced mice did not survive as long as scrambled sequence injected controls (22.2% vs. 50.0% 14 days after cecal ligation and puncture, respectively). When we used a pharmacological/synthetic antagonist of RIP1 kinase, necrostatin 1 (Nec1), and examined the mortality of Nec1-treated mice, there was no difference from the RIP1 siRNA-treated mice (20.0% vs. 22.2%, respectively). Furthermore, we carried out a series of comparative histological studies, which indicated that septic mice pretreated with Nec1 exhibited a preservation of liver glycogen stores (represented by periodic acid Schiff stain) versus siRNA-treated mice, which exhibit lower glycogen stores as well as altered morphology. Furthermore, the histological studies also revealed that Nec1 treatment in septic mice increases caspase 3 activity. We speculate that these contradictatory findings are due to the dual-signaling responsibilities of RIP1, where the RIP1 kinase domain can induce death through Fas ligation while also initiating prosurvival signaling through nuclear factor κB (NF-κB).
    Shock (Augusta, Ga.) 05/2011; 35(5):499-505. DOI:10.1097/SHK.0b013e31820b2db1 · 2.73 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The association between metabolic syndrome and cardiovascular diseases raises important questions about the underlying pathological processes, especially for designing targeted therapeutic interventions. The Peroxisome Proliferators Activated Receptors (PPARs) are ligand-activated transcription factors that control lipid and glucose metabolism. Accumulating data suggest that PPARs may serve as potential targets for treating metabolic diseases and their cardiovascular complications. PPARs regulate gene expression by binding with RXR as a heterodimeric partner to specific DNA sequences, termed PPAR response elements. In addition, PPARs may modulate gene transcription also by directly interfering with other transcription factor pathways in a DNA-binding independent manner. To date, three different PPAR isoforms, designated α, β/δ and γ, have been identified. PPARα and PPARγ are the most extensively examined and characterized, mainly because they are activated by compounds, such as fibrates and thiazolidinediones, that are in clinical use for the treatment of hypertriglyceridemia and insulin resistance, respectively. In contrast the role of PPARβ/δ in metabolism has been less investigated. The recent availability of specific PPARβ/δ agonists revealed that PPARβ/δ plays a crucial role in fatty acid metabolism in several tissues. Besides, PPARβ/δ activation exerts beneficial effects against organ-related ischemic events, such as myocardial and cerebral infarction, which are among the most critical cardiovascular complications evoked by metabolic dysregulation. This paper reviews the evidence and recent developments relating to the potential therapeutic effects of PPARβ/δ agonists in the treatment of metabolic syndrome and its associated cardiovascular risk factors.
    06/2011; 11(4):273-84. DOI:10.2174/187153011797881175
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) is a promising drug target since its agonists increase serum high-density lipoprotein; decrease low-density lipoprotein, triglycerides, and insulin associated with metabolic syndrome; improve insulin sensitivity; and decrease high fat diet-induced obesity. PPARβ/δ agonists also promote terminal differentiation and elicit anti-inflammatory activities in many cell types. However, it remains to be determined whether PPARβ/δ agonists can be developed as therapeutics because there are reports showing either pro- or anti-carcinogenic effects of PPARβ/δ in cancer models. This review examines studies reporting the role of PPARβ/δ in colon, breast, and lung cancers. The prevailing evidence would suggest that targeting PPARβ/δ is not only safe but could have anti-carcinogenic protective effects.
    CANCER AND METASTASIS REVIEW 12/2011; 30(3-4):619-40. DOI:10.1007/s10555-011-9320-1 · 6.45 Impact Factor
Show more