PPAR Agonists Amplify iNOS Expression While Inhibiting NF-κB: Implications for Mesangial Cell Activation by Cytokines
01 Sep 2002-Journal of The American Society of Nephrology (American Society of Nephrology)-Vol. 13, Iss: 9, pp 2223-2231
TL;DR: Experimental data demonstrating that PPAR agonists amplify cytokine-elicited NO generation in MC, potentiating iNOS protein expression approximately threefold show that, despite reducing NF-kappaB activity, PPar agonists may amplify the expression of certain NF- kappaB-dependent genes that are relevant to the inflammatory process, like iN OS.
Abstract: In acute inflammation, the transcription factor NF-kappaB is activated and increases the expression of multiple pro-inflammatory genes. Agonists of peroxisome proliferator activated receptors (PPAR) have been reported to exert antiinflammatory effects in various systems. In keeping with such an antiinflammatory role, it was found that several PPAR agonists, including Wy14,643, clofibrate, carbaprostacyclin, and ciglitazone inhibited NF-kappaB activity and increased IkappaBalpha levels in cytokine-stimulated mesangial cells (MC). Activation of NF-kappaB has been found to be crucial to the cytokine-elicited expression of inducible nitric oxide synthase (iNOS). Despite the inhibitory effect of PPAR agonists on NF-kappaB activity, this study provides experimental data demonstrating that these agonists amplify cytokine-elicited NO generation in MC, potentiating iNOS protein expression approximately threefold. The upregulation of iNOS expression occurred at the mRNA level and apparently did not result from iNOS mRNA stabilization. Clofibrate and ciglitazone amplified the cytokine-elicited stimulation of a 16-Kb human iNOS promoter construct in stably transfected MC, suggesting that PPAR agonists potentiate iNOS induction through transcriptional mechanisms. MC express all three PPAR proteins. However, iNOS potentiation did not correlate with increased PPAR activity. In addition, Wy14,643-induced amplification of cytokine-elicited iNOS levels also occurred in RAW264.7 macrophages and in human epithelial Caco-2 and HT-29 cells. The observation that these epithelial cell lines express an inactive, truncated PPARalpha variant suggests that a classical PPARalpha agonist, such as Wy14,643, may act through PPARalpha-independent mechanisms. In conclusion, these results show that, despite reducing NF-kappaB activity, PPAR agonists may amplify the expression of certain NF-kappaB-dependent genes that are relevant to the inflammatory process, like iNOS.
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Cites background from "PPAR Agonists Amplify iNOS Expressi..."
...…by interacting with its subunits, competing for common transcription coactivators or through upregulation of its inhibitory protein, inhibitor kBa (Cernuda-Morollon et al, 2002; Delerive et al, 2000; Dowell et al, 1997; Gelman et al, 1999; Heneka et al, 2003; Li et al, 2000; Nolte et al, 1998)....
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...It was previously reported that PPAR- agonists, including Wy-14643, clofibrate, carbaprostacyclin, and ciglitazone, inhibited NF- B activity by prevention of I B from phosphorylation and subsequent degradation in cytokine-stimulated mesangial cells (6)....
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References
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TL;DR: It is shown that PPAR-γ is markedly upregulated in activated macrophages and inhibits the expression of the inducible nitric oxide synthase, gelatinase B and scavenger receptor A genes in response to 15d-PGJ2 and synthetic PPar-γ ligands, suggesting that PPARS and locally produced prostaglandin D2 metabolites are involved in the regulation of inflammatory responses.
Abstract: The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors that is predominantly expressed in adipose tissue, adrenal gland and spleen PPAR-gamma has been demonstrated to regulate adipocyte differentiation and glucose homeostasis in response to several structurally distinct compounds, including thiazolidinediones and fibrates Naturally occurring compounds such as fatty acids and the prostaglandin D2 metabolite 15-deoxy-delta prostaglandin J2 (15d-PGJ2) bind to PPAR-gamma and stimulate transcription of target genes Prostaglandin D2 metabolites have not yet been identified in adipose tissue, but are major products of arachidonic-acid metabolism in macrophages, raising the possibility that they might serve as endogenous PPAR-gamma ligands in this cell type Here we show that PPAR-gamma is markedly upregulated in activated macrophages and inhibits the expression of the inducible nitric oxide synthase, gelatinase B and scavenger receptor A genes in response to 15d-PGJ2 and synthetic PPAR-gamma ligands PPAR-gamma inhibits gene expression in part by antagonizing the activities of the transcription factors AP-1, STAT and NF-kappaB These observations suggest that PPAR-gamma and locally produced prostaglandin D2 metabolites are involved in the regulation of inflammatory responses, and raise the possibility that synthetic PPAR-gamma ligands may be of therapeutic value in human diseases such as atherosclerosis and rheumatoid arthritis in which activated macrophages exert pathogenic effects
3,587 citations
"PPAR Agonists Amplify iNOS Expressi..." refers background or result in this paper
...Overexpression of PPAR was required in several studies to observe the inhibitory effects of PPAR agonists on the activity of iNOS promoter reporter constructs, although either no effect or an increase in the activity of the iNOS promoter could be observed in the absence of PPAR overexpression (22,47)....
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...The observation that various PPAR agonists amplify iNOS induction is in apparent contradiction with several reports that have proposed a negative role for PPAR activation on iNOS expression (22,47)....
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...Certain PPAR agonists have been reported to attenuate iNOS induction in murine macrophages (22,23,36), whereas others amplify it in macrophages or in smooth muscle cells (36,37)....
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...PPAR have also been reported to interfere with the activity of transcription factors, such as AP-1, NF- B, or STAT-1 (22), which are critically involved in the signal transduction of cytokines, lipopolysaccharides (LPS), and interferons (IFN), either by competing for limiting amounts of general co-activators (23) or by direct protein-protein interaction (24)....
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...In numerous experimental systems, a correlation between the inhibitory effects of PPAR and a reduction in NF- B activity has been observed (10,22,25)....
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TL;DR: Inhibition of cytokine production may help to explain the incremental therapeutic benefit of NSAIDs observed in the treatment of rheumatoid arthritis at plasma drug concentrations substantially higher than are required to inhibit prostaglandin G/H synthase (cyclooxygenase).
Abstract: The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor family of transcription factors, a large and diverse group of proteins that mediate ligand-dependent transcriptional activation and repression Expression of PPAR-gamma is an early and pivotal event in the differentiation of adipocytes Several agents that promote differentiation of fibroblast lines into adipocytes have been shown to be PPAR-gamma agonists, including several prostanoids, of which 15-deoxy-delta-prostaglandin J2 is the most potent, as well as members of a new class of oral antidiabetic agents, the thiazolidinediones, and a variety of non-steroidal anti-inflammatory drugs (NSAIDs) Here we show that PPAR-gamma agonists suppress monocyte elaboration of inflammatory cytokines at agonist concentrations similar to those found to be effective for the promotion of adipogenesis Inhibition of cytokine production may help to explain the incremental therapeutic benefit of NSAIDs observed in the treatment of rheumatoid arthritis at plasma drug concentrations substantially higher than are required to inhibit prostaglandin G/H synthase (cyclooxygenase)
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TL;DR: A pivotal role is suggested for PPARγ and its endogenous ligand in adipocyte development and glucose homeostasis and as a target for intervention in metabolic disorders.
2,809 citations
TL;DR: Evidence that PPARs serve as physiological sensors of lipid levels is provided and a molecular mechanism whereby dietary fatty acids can modulate lipid homeostasis is suggested.
Abstract: Peroxisome proliferator-activated receptors (PPARs) alpha and gamma are key regulators of lipid homeostasis and are activated by a structurally diverse group of compounds including fatty acids, eicosanoids, and hypolipidemic drugs such as fibrates and thiazolidinediones. While thiazolidinediones and 15-deoxy-Delta12, 14-prostaglandin J2 have been shown to bind to PPARgamma, it has remained unclear whether other activators mediate their effects through direct interactions with the PPARs or via indirect mechanisms. Here, we describe a novel fibrate, designated GW2331, that is a high-affinity ligand for both PPARalpha and PPARgamma. Using GW2331 as a radioligand in competition binding assays, we show that certain mono- and polyunsaturated fatty acids bind directly to PPARalpha and PPARgamma at physiological concentrations, and that the eicosanoids 8(S)-hydroxyeicosatetraenoic acid and 15-deoxy-Delta12,14-prostaglandin J2 can function as subtype-selective ligands for PPARalpha and PPARgamma, respectively. These data provide evidence that PPARs serve as physiological sensors of lipid levels and suggest a molecular mechanism whereby dietary fatty acids can modulate lipid homeostasis.
2,054 citations
TL;DR: The latest developments in the PPAR field are presented, with particular emphasis on the physiological function ofPPARs during various nutritional states, and the possible role of PPARs in several chronic diseases.
Abstract: In developed societies, chronic diseases such as diabetes, obesity, atherosclerosis and cancer are responsible for most deaths These ailments have complex causes involving genetic, environmental and nutritional factors There is evidence that a group of closely related nuclear receptors, called peroxisome proliferator-activated receptors (PPARs), may be involved in these diseases This, together with the fact that PPAR activity can be modulated by drugs such as thiazolidinediones and fibrates, has instigated a huge research effort into PPARs Here we present the latest developments in the PPAR field, with particular emphasis on the physiological function of PPARs during various nutritional states, and the possible role of PPARs in several chronic diseases
1,895 citations
"PPAR Agonists Amplify iNOS Expressi..." refers background or methods in this paper
...Confluent MC, stably transfected with a 16-Kb reporter construct of the human iNOS promoter, were treated with IL-1 /TNF- (Ck) in the absence or presence of PPAR agonists as indicated: (1) vehicle; (2) 25 M Wy14,643; (3) 100 M clofibrate; (4) 5 M ciglitazone....
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...The ligand-activated transcription factors that are known as peroxisome proliferator activated receptors (PPAR), previously accepted to control lipid metabolism and adipocyte differentiation, have received considerable attention due to their recently identified role as modulators of vascular pathophysiology (1)....
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