PPARδ-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis

Takata, Yasunori; Liu, Joey; Yin, Fen; Collins, Alan R.; Lyon, Christopher J.; Lee, Chih‐Hao; Atkins, Annette R.; Downes, Michael; Barish, Grant D.; Evans, Ronald M.; Hsueh, Willa A.; Tangirala, Rajendra K.

doi:10.1073/pnas.0708647105

Cited by 198 publications

(195 citation statements)

References 39 publications

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“…Other studies using PPARδ ligand have shown a reduction of inflammatory gene expression but not a decrease in atherosclerosis in LDLR −/− mice challenge with hypercholesterolemic diet [22]. Recently, Takata et al reported a reduction in atherosclerosis by PPARδ ligand in an angiotensin II accelerated LDLR −/− model [24].…”

Section: Ppars and Inflammationmentioning

confidence: 95%

Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors

Hong

Tontonoz

2008

Current Opinion in Genetics & Development

206

153

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Biological systems are integrated networks constantly responding to internal and external stimulators. Understanding the intrinsic response to an imbalanced system provides the opportunity to develop therapeutic approaches to reinstate the natural balanced state. Increasing evidence suggests that members of the nuclear receptor superfamily integrate both inflammatory and metabolic signals to maintain homeostasis in immune cells such as macrophages and lymphocytes. PPAR and LXR are nuclear receptors activated by fatty acid and cholesterol derivatives respectively that control the expression of an array of genes involved in lipid metabolism and inflammation. Recent studies have uncovered distinct mechanisms for transcriptional regulation of metabolic and inflammatory target genes by PPAR and LXR and have expanded the biology of these receptors to include roles in alternative macrophage activation and adaptive immunity.

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Section: Ppars and Inflammationmentioning

confidence: 95%

Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors

Hong

Tontonoz

2008

Current Opinion in Genetics & Development

206

153

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“…anti-inflammatory role of PPARδ in CS-related airway inflammation. It has been found that treatment with a synthetic PPARδ agonist inhibited activation of p38 MAP kinases in inflammatory circumstance, 19,28,32 which suggested a tight link between PPARδ and p38 MAPK. The MAPK family includes three members: p38, ERK and c-Jun N-terminal kinase (JNK).…”

Section: Discussionmentioning

confidence: 99%

“…WNT/β-Catenin Signaling Pathway Regulated CS-Stimulated Airway Inflammation by a PPARδ/p38 MAPK-Dependent Manner PPARδ, which has been reported to be involved in inflammation, 21,28 was a downstream target gene of WNT/ β-catenin signaling. 16 Our PCR results in Figure 3 showed that the mRNA levels of PPARδ were decreased by CSE stimulation.…”

Section: Cse-induced Inflammatory Cytokine Release Dependent On Wnt/βmentioning

confidence: 99%

WNT/β-catenin signaling regulates cigarette smoke-induced airway inflammation via the PPARδ/p38 pathway

Guo

Wang

et al. 2016

Laboratory Investigation

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The mechanisms of WNT/β-catenin signaling involved in airway inflammation of chronic obstructive pulmonary disease (COPD) remain unknown, although recent observations have suggested an important contribution of the pathway in pulmonary parenchymal tissue repair and airway epithelium differentiation. We investigated the role of WNT/β-catenin signaling in cigarette smoke (CS)-related airway inflammation using patient lung tissues, human bronchial epithelial cells (16HBECs), and mouse models. Reduced activity of WNT/β-catenin signaling was observed in the airway epithelium of smokers with or without COPD. The mRNA expression of WNT transcription factor TCF4 negatively correlated with the pack year. The mRNA levels of WNT receptor FZD4 negatively correlated with the mRNA levels of IL-1β. CS exposure decreased the activity of WNT/β-catenin signaling in both 16HBECs and mice. In vitro studies demonstrated the upregulation of inflammatory cytokines TNF-α and IL-1β secretion induced by CS extract (CSE) could be attenuated by β-catenin activator SB216763 and be exacerbated by β-catenin small-interfering RNA (siRNA), respectively. Furthermore, the decrease in the expression of peroxisome proliferator-activated receptor (PPARδ) induced by CSE stimulation could be rescued by SB216763. SB216763 also attenuated the upregulation of phosphorylated p38 mitogen-activated protein kinase (MAPK) stimulated by CSE. Both PPARδ agonist and p38 MAPK inhibitor could suppress the TNF-α and IL-1β release induced by CSE treatment. In addition, PPARδ activation could abolish β-catenin siRNA-mediated aggravation of phosphorylated p38 MAPK in response to CSE. Finally, SB216763 treatment significantly ameliorated peribronchial inflammatory cell infiltration, leukocyte influx, and the release of TNF-α and IL-1β in the bronchoalveolar lavage fluid of CS-exposed mice. Taken together, our findings indicate that the reduced activity of WNT/β-catenin signaling induced by CS may promote inflammatory cytokine production in airway epithelium and have an essential role in airway inflammation in COPD by PPARδ/p38 MAPK pathway.

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“…PPARβ/δ -/-naïve CD4 + T cells are more prone to Th17 differentiation and hyper-responsive to TCR stimulation, as evidenced by the increased proliferation observed in these cells. Interestingly, PPARβ/δ has been hypothesized to bind the transcription factor B cell lymphoma 6 A B C (BCL6) and repress inflammation-related gene expression Takata et al, 2008;Varga et al, 2011).…”

Section: Ppars In T Cells and Autoimmunitymentioning

confidence: 99%

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

Choi¹,

Bothwell

2012

Molecules and Cells

149

111

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Members of the nuclear receptor superfamily function as transcription factors involved in innate and adaptive immunity as well as lipid metabolism. These highly conserved proteins participate in ligand-dependent or -independent regulatory mechanisms that affect gene expression. Peroxisome proliferator-activated receptors (PPARs), which include PPARα, PPARβ/δ, and PPARγ, are a group of nuclear receptor proteins that play diverse roles in cellular differentiation, development, and metabolism. Each PPAR subfamily is activated by different endogenous and synthetic ligands. Recent studies using specific ligand treatments and cell type-specific PPAR knockout mice have revealed important roles for these proteins in T-cell-related autoimmune diseases. Moreover, PPARs have been shown to regulate T-cell survival, activation, and CD4 + T helper cell differentiation into the Th1, Th2, Th17, and Treg lineages. Here, we review the studies that provide insight into the important regulatory roles of PPARs in T-cell activation, survival, proliferation, differentiation, and autoimmune disease.

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PPARδ-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis

Cited by 198 publications

References 39 publications

Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors

Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors

WNT/β-catenin signaling regulates cigarette smoke-induced airway inflammation via the PPARδ/p38 pathway

The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases

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