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Biomedical subjects

B Staels

Publications and source records attributed to B Staels.

At least 19 recordsLinked to original sources
PubMed2001

The role of fibric acids in atherosclerosis.

The hypolipidemic fibric acid drugs are peroxisome proliferator-activated receptor a (PPAR alpha) ligands. PPAR alpha activated by fibric acids form heterodimers with the 9-cis retinoic acid receptor (RXR). The PPAR/RXR heterodimers bind to peroxisome proliferator response elements (PPRE), which are located in numerous gene promoters and increase the level of the expression of mRNAs encoded by PPAR alpha target genes. Fibric acids decrease triglyceride plasma levels through increases in the expression of genes involved in fatty acid-beta oxidation. Furthermore, they decrease triglycerides by increasing lipoprotein lipase gene expression and by decreasing apolipoprotein C-III gene expression. Fibric acids increase high-density lipoprotein (HDL) cholesterol partly by increasing apolipoprotein A-I and apolipoprotein A-II gene expression. Fibric acids also reduce vascular wall inflammation and the expression of genes involved in different vascular functions (ie, vasomotricity, thrombosis). Fibric acids are used to treat primary hypertriglyceridemia and mixed hyperlipidemia. Some fibric acid molecules are active in essential hypercholesterolemia. Clinical evidence shows that fibric acids reduce coronary atherosclerosis progression in dyslipidemic patients (eg, bezafibrate, gemfibrozil) and in type 2 diabetic patients (fenofibrate). Gemfibrozil decreases coronary morbidity and mortality in patients with low HDL cholesterol, normal triglycerides,and normal low-density lipoprotein (LDL) cholesterol plasma levels. Further clinical studies are necessary to investigate if fibric acids decrease cardiovascular mortality in type 2 diabetes and in primary prevention of hypertriglyceridemia and hypolipidemia.

Arteriosclerosis↗
PubMed2001

PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate lipid and glucose metabolism and cellular differentiation. PPAR-alpha and PPAR-gamma are both expressed in human macrophages where they exert anti-inflammatory effects. The activation of PPAR-alpha may promote foam-cell formation by inducing expression of the macrophage scavenger receptor CD36. This prompted us to investigate the influence of different PPAR-activators on cholesterol metabolism and foam-cell formation of human primary and THP-1 macrophages. Here we show that PPAR-alpha and PPAR-gamma activators do not influence acetylated low density lipoprotein-induced foam-cell formation of human macrophages. In contrast, PPAR-alpha and PPAR-gamma activators induce the expression of the gene encoding ABCA1, a transporter that controls apoAI-mediated cholesterol efflux from macrophages. These effects are likely due to enhanced expression of liver-x-receptor alpha, an oxysterol-activated nuclear receptor which induces ABCA1-promoter transcription. Moreover, PPAR-alpha and PPAR-gamma activators increase apoAI-induced cholesterol efflux from normal macrophages. In contrast, PPAR-alpha or PPAR-gamma activation does not influence cholesterol efflux from macrophages isolated from patients with Tangier disease, which is due to a genetic defect in ABCA1. Here we identify a regulatory role for PPAR-alpha and PPAR-gamma in the first steps of the reverse-cholesterol-transport pathway through the activation of ABCA1-mediated cholesterol efflux in human macrophages.

ATP Binding Cassette Transporter 1↗
PubMed2000

Peroxisome proliferator-activated receptor gamma activators inhibit interleukin-12 production in murine dendritic cells.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily. They are divided into three subtypes (alpha, beta or delta, and gamma) and are involved in lipid and glucose homeostasis and in the control of inflammation. In this study, we analyzed the expression of PPARs in murine dendritic cells (DCs), the most potent antigen presenting cells. We find that immature as well as mature spleen-derived DCs express PPARgamma, but not PPARalpha, mRNA and protein. We also show that the PPARgamma activator rosiglitazone does not interfere with the maturation of DCs in vitro nor modifies their ability to activate naive T lymphocytes in vivo. Finally, we present evidence that PPARgamma activators down-modulate the CD40-induced secretion of interleukin-12, a potent Th1-driving factor. These data suggest a possible role for PPARgamma in the regulation of immune responses.

Animals↗
PubMed2000

Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators.

Chronic inflammation is a hallmark of degenerative diseases such as atherosclerosis. Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily, which are expressed in the cells of the atherosclerosic lesion. PPARalpha ligands have been reported to exert anti-inflammatory activities in different cell types by antagonizing the transcriptional activity of NF-kappaB. In the present study, the influence of PPARalpha activators on the NF-kappaB signaling pathway was investigated. Our results show that fibrates, synthetic PPARalpha activators, induced the expression of the inhibitory protein IkappaBalpha in human aortic smooth muscle cells as well as in primary human hepatocytes, whereas neither IkappaB-kinase activity nor the degradation rate of IkappaBalpha were affected. Using PPARalpha-null mice, we demonstrated that fibrates induced IkappaBalpha in liver in vivo and that this action required PPARalpha. Furthermore, fibrate treatment induced IkappaBalpha protein expression in the cytoplasm and also enhanced IL-1beta-induced accumulation of IkappaBalpha protein in the nucleus. These actions of fibrates on IkappaBalpha expression were accompanied by a decrease in NF-kappaB DNA binding activity as demonstrated by electrophoretic mobility shift assays. Taken together, these data provide an additional molecular mechanism for the anti-inflammatory activity of PPARalpha agonists and reinforce their potential use in the treatment of inflammatory diseases.

Animals↗
PubMed2000

Transcriptional regulation of apolipoprotein C-III gene expression by the orphan nuclear receptor RORalpha.

Triglyceride-rich remnant lipoproteins are considered as major risk factors contributing to the pathogenesis of atherosclerosis. Because apolipoprotein (apo) C-III is a major determinant of plasma triglyceride and remnant lipoprotein metabolism, it is important to understand how the expression of this gene is regulated. In the present study, we identified the orphan nuclear receptor RORalpha1 as a regulator of human and mouse apo C-III gene expression. Plasma triglyceride and apo C-III protein concentrations in staggerer (sg/sg) mice, homozygous for a deletion in the RORalpha gene, were significantly lower than in wild type littermates. The lowered plasma apo C-III levels were associated with reduced apo C-III mRNA levels in liver and intestine of sg/sg mice. Transient transfection experiments in human hepatoma HepG2, human colonic CaCO2, and rabbit kidney RK13 cells demonstrated that overexpression of the human RORalpha1 isoform specifically increases human apo C-III promoter activity, indicating that RORalpha1 enhances human apo C-III gene transcription. RORalpha1 response elements were mapped by promoter deletion analysis and gel shift experiments to two AGGTCA half-sites located at positions -83/-78 (within the C3P site) and -23/-18 (downstream of the TATA box) in the human apo C-III promoter, with the -23/-18 site exhibiting the highest binding affinity. Transfection of site-directed mutated constructs in HepG2 cells indicated that the RORalpha1 effect is predominantly mediated by the -23/-18 site. This site is conserved in the mouse apo C-III gene promoter. Moreover, RORalpha binds to the equivalent mouse site and activates constructs containing three copies of the mouse site cloned in front of an heterologous promoter. Taken together, our data identify RORalpha as a transcriptional regulator of apo C-III gene expression, providing a novel, physiological role for RORalpha1 in the regulation of genes controlling triglyceride metabolism.

Animals↗
PubMed2000

Peroxisome proliferator-activated receptor alpha is not rate-limiting for the lipoprotein-lowering action of fish oil.

Similar to fibrate hypolipidemic drugs, long chain polyunsaturated fatty acids contained in fish oil are activators of peroxisome proliferator-activated receptor alpha (PPARalpha). The goal of this study was to assess the contribution of PPARalpha in mediating the effect of fish oil on plasma lipid, lipoprotein, and apolipoprotein levels. To this end, PPARalpha-deficient mice and wild-type littermates were fed isocaloric fish oil or coconut oil diets, the content of which varied reciprocally between 0, 3, 7, and 10% for 1 week. In both wild-type and PPARalpha-deficient mice, fish oil feeding was associated with a dose-dependent decrease in triglycerides, cholesterol, and phospholipids associated with lower levels of very low density lipoprotein (VLDL) triglycerides and high density lipoprotein (HDL) cholesterol. The lowering of triglycerides and VLDL triglycerides was associated with a significant decrease of plasma apoC-III in both genotypes. Fish oil treatment did not influence hepatic apoC-III mRNA levels in either genotype indicating that apoC-III is not under transcriptional control by fish oil. The lowering of HDL cholesterol observed in both genotypes was associated with reduced plasma apoA-II without changes in liver apoA-II mRNA levels. In contrast, plasma apoA-I and liver apoA-I mRNA levels were decreased in wild-type but not in PPARalpha-deficient mice after fish oil feeding indicating that PPARalpha contributes to the effect of fish oil on apoA-I gene expression. In conclusion, PPARalpha is not rate-limiting for fish oil to exert its triglyceride- and HDL-lowering action. Furthermore, PPARalpha mediates, at least partly, the decrease of apoA-I after fish oil treatment, whereas apoC-III and apoA-II levels are affected in a PPARalpha-independent manner. Altogether, these results show major molecular differences in action between fibrates and fish oil providing a molecular rationale for combination treatment with these compounds.

Acyl-CoA Oxidase↗
PubMed2000

Role of the peroxisome proliferator-activated receptors (PPAR) in atherosclerosis.

Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors which form a subfamily of the nuclear receptor gene family. PPAR activators have effects on both metabolic risk factors and on vascular inflammation related to atherosclerosis. PPAR have profound effects on the metabolism of lipoproteins and fatty acids. PPAR alpha binds hypolipidemic fibrates, whereas PPAR gamma has a high affinity for antidiabetic glitazones. Both PPAR are activated by fatty acids and their derivatives. Activation of PPAR alpha increases the catabolism of fatty acids at several levels. In the liver, it increases uptake of fatty acids and activates their beta-oxidation. The effects that PPAR alpha exerts on triglyceride-rich lipoproteins is due to their stimulation of lipoprotein lipase and repression of apolipoprotein CIII expression, while the effects on high-density lipoproteins depend upon the regulation of apolipoproteins AI and AII. PPAR gamma has profound effects on the differentiation and function of adipose tissue, where it is highly expressed. PPAR are also expressed in atherosclerotic lesions. PPAR are present in vascular endothelial cells, smooth muscle cells, monocytes, and monocyte-derived macrophages. Via negative regulation of nuclear factor-kappa B and activator protein-1 signalling pathways, PPAR alpha inhibits expression of inflammatory genes, such as interleukin-6, cyclooxygenase-2, and endothelin-1. Furthermore, PPAR alpha inhibits expression of monocyte-recruiting proteins such as vascular cell adhesion molecule (VCAM)-1 and induces apoptosis in monocyte-derived macrophages. PPAR gamma activation in macrophages and foam cells inhibits the expression of activated genes such as inducible nitric oxide synthase, matrix metalloproteinase-9 and scavenger receptor A. PPAR gamma may also affect the recruitment of monocytes in atherosclerotic lesions as it is involved in the expression of VCAM-1 and intracellular adhesion molecule-1 in vascular endothelial cells. The involvement of PPAR in atherosclerosis, a disease with a chronic inflammatory character, suggests that they may play a role in other inflammatory-related diseases as well.

Arteriosclerosis↗
PubMed2000

Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity.

Fibrates and glitazones are two classes of drugs currently used in the treatment of dyslipidemia and insulin resistance (IR), respectively. Whereas glitazones are insulin sensitizers acting via activation of the peroxisome proliferator-activated receptor (PPAR) gamma subtype, fibrates exert their lipid-lowering activity via PPARalpha. To determine whether PPARalpha activators also improve insulin sensitivity, we measured the capacity of three PPARalpha-selective agonists, fenofibrate, ciprofibrate, and the new compound GW9578, in two rodent models of high fat diet-induced (C57BL/6 mice) or genetic (obese Zucker rats) IR. At doses yielding serum concentrations shown to activate selectively PPARalpha, these compounds markedly lowered hyperinsulinemia and, when present, hyperglycemia in both animal models. This effect relied on the improvement of insulin action on glucose utilization, as indicated by a lower insulin peak in response to intraperitoneal glucose in ciprofibrate-treated IR obese Zucker rats. In addition, fenofibrate treatment prevented high fat diet-induced increase of body weight and adipose tissue mass without influencing caloric intake. The specificity for PPARalpha activation in vivo was demonstrated by marked alterations in the expression of PPARalpha target genes, whereas PPARgamma target gene mRNA levels did not change in treated animals. These results indicate that compounds with a selective PPARalpha activation profile reduce insulin resistance without having adverse effects on body weight and adipose tissue mass in animal models of IR.

Adipose Tissue↗
PubMed2000

CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and regulated by activators of peroxisome proliferator-activated receptors.

BACKGROUND: The scavenger receptors are cell-surface receptors for native and modified lipoproteins that play a critical role in the accumulation of lipids by macrophages. CLA-1/SR-BI binds HDL with high affinity and is involved in the cholesterol reverse-transport pathway. Peroxisome proliferator-activated receptors (PPARs) are transcription factors regulating the expression of genes implicated in lipid metabolism, cellular differentiation, and inflammation. Here, we investigated the expression of CLA-1/SR-BI in macrophages and its regulation by PPARs. METHODS AND RESULTS: CLA-1 is undetectable in human monocytes and is induced upon differentiation into macrophages. Immunohistological analysis on human atherosclerotic lesions showed high expression of CLA-1 in macrophages of the lipid core colocalizing with PPARalpha and PPARgamma staining. Activation of PPARalpha and PPARgamma resulted in the induction of CLA-1 protein expression in monocytes and in differentiated macrophages. Finally, SR-BI expression is increased in atherosclerotic lesions of apoE-null mice treated with either PPARgamma or PPARalpha ligands. CONCLUSIONS: Our data demonstrate that CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and induced by PPAR activation, identifying a potential role for PPARs in cholesterol homeostasis in atherosclerotic lesion macrophages.

Animals↗
PubMed2000

Oxidized phospholipids activate PPARalpha in a phospholipase A2-dependent manner.

The peroxisome proliferator-activated receptor alpha (PPARalpha) is a transcription factor belonging to the PPAR subfamily of nuclear receptors. Fatty acids and eicosanoids are natural PPARalpha ligands. Here, we show using transient transfection assays that oxidized (oxLDL) but not native low-density lipoproteins (LDL) dose-dependently activate PPARalpha in endothelial cells without affecting PPARalpha protein expression. Fractioning of oxLDL lipids followed by transactivation experiments demonstrated that the oxidized phospholipid component in oxLDL is responsible for PPARalpha activation. Using specific inhibitors, it is shown that oxLDL-mediated PPARalpha activation requires phospholipase A2 activity and that the oxidized fatty acids 9- and 13-HODE activate PPARalpha directly. Finally, we found that, similar to the synthetic PPARalpha ligand Wy-14643, oxLDL induced expression of the fatty acid transport protein-1 in human primary endothelial cells. Our findings define a novel group of PPARalpha activators and provide a molecular basis for certain effects of these biologically active phospholipids on gene transcription.

Carrier Proteins↗
PubMed2000

Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation.

Peroxisome proliferator-activated (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor family. PPARs function as regulators of lipid and lipoprotein metabolism and glucose homeostasis and influence cellular proliferation, differentiation and apoptosis. PPARalpha is highly expressed in tissues such as liver, muscle, kidney and heart, where it stimulates the beta-oxidative degradation of fatty acids. PPARgamma is predominantly expressed in intestine and adipose tissue. PPARgamma triggers adipocyte differentiation and promotes lipid storage. The hypolipidemic fibrates and the antidiabetic glitazones are synthetic ligands for PPARalpha and PPARgamma, respectively. Furthermore, fatty acids and eicosanoids are natural PPAR ligands: PPARalpha is activated by leukotriene B4, whereas prostaglandin J2 is a PPARgamma ligand. These observations suggested a potential role for PPARs not only in metabolic but also in inflammation control. The first evidence for a role of PPARalpha in inflammation control came from the demonstration that PPARalpha deficient mice display a prolonged response to inflammatory stimuli. It was suggested that PPARalpha deficiency results in a reduced beta-oxidative degradation of these inflammatory fatty acid derivatives. More recently, PPAR activators were shown to inhibit the activation of inflammatory response genes (such as IL-2, IL-6, IL-8, TNFalpha and metalloproteases) by negatively interfering with the NF- kappaB, STAT and AP-1 signalling pathways. PPAR activators exert these anti-inflammatory activities in different immunological and vascular wall cell types such as monocyte/macrophages, endothelial, epithelial and smooth muscle cells in which PPARs are expressed. These recent findings indicate a modulatory role for PPARs in the control of the inflammatory response with potential therapeutic applications in inflammation-related diseases, such as atherosclerosis and inflammatory bowel disease.

Acute-Phase Proteins↗
PubMed2000

Variation in the PPARalpha gene is associated with altered function in vitro and plasma lipid concentrations in Type II diabetic subjects.

AIMS/HYPOTHESIS: Peroxisome proliferator activated receptor alpha (PPARalpha) regulates genes involved in lipid metabolism, haemostasis and inflammation, in response to fatty acids and fibrates, making it a candidate gene for risk of dyslipidaemia, atherosclerosis and coronary artery disease. Plasma non-esterified fatty acids are increased in subjects with Type II (non-insulin-dependent) diabetes mellitus, suggesting that PPARalpha could link Type II diabetes and dyslipidaemia, and affect response to fibrates. This has been investigated in association studies in healthy and diabetic subjects and in vitro studies. METHODS: The human PPARalpha gene was isolated and screened for variation by single strand conformation polymorphism analysis. Genotypes were determined for 129 Type II diabetic subjects and 2508 healthy men. The association with plasma lipid concentrations was examined. The function of the V162 variant was examined in co-transfection assays. RESULTS: We identified two polymorphisms, one in intron 3 and a missense mutation, leucine 162 to valine, in the DNA binding domain. In Type II diabetic patients, V162 allele carriers had higher total cholesterol, HDL cholesterol and apoAI whereas intron 3 rare allele carriers had higher apoAI concentrations. By contrast, no effect was observed in healthy rare allele carriers. In vitro, the V162 variant showed greater transactivation of a reporter gene construct. CONCLUSION/INTERPRETATION: Naturally occurring variation alters PPARalpha function, influencing plasma lipid concentrations in Type II diabetic patients but not healthy people. This demonstrates that PPARalpha is a link between diabetes and dyslipidaemia, and so could influence the risk of coronary artery disease, the greatest cause of morbidity and mortality in Type II diabetes.

Apolipoprotein A-I↗
PubMed2000

Circadian and glucocorticoid regulation of Rev-erbalpha expression in liver.

Rev-erbalpha [NR1D1], a member of the nuclear receptor superfamily, is an orphan receptor that constitutively represses gene transcription. Rev-erbalpha has been shown to play a role in myocyte differentiation and to be induced during adipogenesis. Furthermore, Rev-erbalpha is a regulator of lipoprotein metabolism. It was recently shown that Rev-erbalpha messenger RNA (mRNA) levels oscillate diurnally in rat liver. Here, we report that the circadian rhythm of Rev-erbalpha in liver is maintained in primary cultures of rat hepatocytes. Because glucocorticoids have been shown to regulate other transcription factors with circadian expression, it was furthermore examined whether hepatic Rev-erbalpha expression is also regulated by glucocorticoids. Treatment of rats with dexamethasone resulted in a decrease of Rev-erbalpha mRNA levels by 70% after 6 h. Furthermore, dexamethasone decreased Rev-erbalpha expression in rat primary hepatocytes in a dose-dependent fashion. This effect was mediated by the glucocorticoid receptor because simultaneous addition of the glucocorticoid antagonist RU486 prevented the decrease in Rev-erbalpha mRNA levels by dexamethasone. Protein synthesis inhibition with cycloheximide markedly induced Rev-erbalpha mRNA levels; however, this induction was reduced by dexamethasone supplementation in both rat and human primary hepatocytes. Treatment with actinomycin D blocked the repression of Rev-erbalpha expression by dexamethasone in rat hepatocytes, suggesting that glucocorticoids regulate Rev-erbalpha expression at the transcriptional level. Transient transfection experiments further indicated that Rev-erbalpha promoter activity is repressed by dexamethasone in the presence of cotransfected glucocorticoid receptor. Taken together, these data demonstrate that Rev-erbalpha expression is under the control of both the circadian clock and glucocorticoids in the liver.

Animals↗
PubMed2000

Regulation of lipid and lipoprotein metabolism by PPAR activators.

The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. PPARalpha, the first identified PPAR family member, is principally expressed in tissues exhibiting high rates of beta-oxidation such as liver, kidney, heart and muscle. PPARgamma, on the other hand, is expressed at high levels in adipose tissue. PPARs are activated by dietary fatty acids and eicosanoids, as well as by pharmacological drugs, such as fibrates for PPARalpha and glitazones for PPARgamma. PPARalpha mediates the hypolipidemic action of fibrates in the treatment of hypertriglyceridemia and hypoalphalipoproteinemia. PPARalpha is considered a major regulator of intra- and extracellular lipid metabolism. Upon fibrate activation, PPARalpha down-regulates hepatic apolipoprotein C-III and increases lipoprotein lipase gene expression, key players in triglyceride metabolism. In addition, PPARalpha activation increases plasma HDL cholesterol via the induction of hepatic apolipoprotein A-I and apolipoprotein A-II expression in humans. Glitazones exert a hypotriglyceridemic action via PPARgamma-mediated induction of lipoprotein lipase expression in adipose tissue. PPARs play also a role in intracellular lipid metabolism by up-regulating the expression of enzymes involved in conversion of fatty acids in acyl-coenzyme A esters, fatty acid entry into mitochondria and peroxisomal and mitochondrial fatty acid catabolism. These observations have provided the molecular basis leading to a better understanding of the mechanism of action of fibrates and glitazones on lipid and lipoprotein metabolism and identify PPARs as attractive targets for the rational design of more potent lipid-lowering drugs.

Cell Nucleus↗
PubMed2000

Mutation screening of the PPARalpha gene in type 2 diabetes associated with coronary heart disease.

The peroxisome proliferator-activated receptor alpha (PPARalpha) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. PPARalpha plays a key role in lipid and glucose metabolism, inflammatory response and energy homeostasis. The aim of our study was to screen the PPARalpha gene for mutations, and to test the genetic contribution of PPARalpha in diabetes and its vascular complications. The first two non coding exons and the coding region of the PPARalpha gene were screened by single strand conformation polymorphism (SSCP) and sequencing in 74 unrelated Type 2 diabetic patients with history of coronary heart disease (CHD) (18 Caucasian and 56 Indian subjects). A total of 7 nucleotide variants were detected: two single amino acid substitutions, a silent mutation, four intron base changes. Association studies were undertaken in two populations of Type 2 diabetic patients from Pondichery and from France, to test the distribution of allelic frequencies for L162V (exon 5) and A268V (exon 7) polymorphisms. No association was found between these PPARalpha variants and diabetes or CHD. However, in the Caucasian diabetic male population with CHD, the Val162 allele carriers showed higher concentrations of total cholesterol and Apo B when compared to non-carriers (p =0.01 and p =0.005, respectively). A trend toward elevated concentrations of total cholesterol and Apo B was also observed in the Caucasian diabetic male patients without CHD carrying Val162 allele. In conclusion, it is likely that PPARalpha gene does not have a major role in diabetes and CHD in our populations, although we can not exclude a minor contribution of the PPARalpha gene to the risk of CHD associated with Type 2 diabetes through a modulation of atherogenic plasma lipids.

Amino Acid Substitution↗
PubMed1999

Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1.

Interleukin-6 (IL-6) is a pleiotropic cytokine, whose plasma levels are elevated in inflammatory diseases such as atherosclerosis. We have previously reported that peroxisome proliferator-activated receptor alpha (PPARalpha) ligands (fibrates) lower elevated plasma concentrations of IL-6 in patients with atherosclerosis and inhibit IL-1-stimulated IL-6 secretion by human aortic smooth muscle cells (SMC). Here, we show that aortic explants isolated from PPARalpha-null mice display an exacerbated response to inflammatory stimuli, such as lipopolysaccharide (LPS), as demonstrated by increased IL-6 secretion. Furthermore, fibrate treatment represses IL-6 mRNA levels in LPS-stimulated aortas of PPARalpha wild-type, but not of PPARalpha-null mice, demonstrating a role for PPARalpha in this fibrate action. In human aortic SMC, fibrates inhibit IL-1-induced IL-6 gene expression. Furthermore, activation of PPARalpha represses both c-Jun- and p65-induced transcription of the human IL-6 promoter. Transcriptional interference between PPARalpha and both c-Jun and p65 occurs reciprocally, since c-Jun and p65 also inhibit PPARalpha-mediated activation of a PPAR response element-driven promoter. This transcriptional interference occurs independent of the promoter context as demonstrated by cotransfection experiments using PPARalpha, p65, and c-Jun Gal4 chimeras. Overexpression of the transcriptional coactivator cAMP-responsive element-binding protein-binding protein (CBP) does not relieve PPARalpha-mediated transcriptional repression of p65 and c-Jun. Finally, glutathione S-transferase pull-down experiments demonstrate that PPARalpha physically interacts with c-Jun, p65, and CBP. Altogether these data indicate that fibrates inhibit the vascular inflammatory response via PPARalpha by interfering with the NF-kappaB and AP-1 transactivation capacity involving direct protein-protein interaction with p65 and c-Jun.

Animals↗
PubMed1999

Protective role of interleukin-10 in atherosclerosis.

The potential role of anti-inflammatory cytokines in the modulation of the atherosclerotic process remains unknown. Interleukin (IL)-10 has potent deactivating properties in macrophages and T cells and modulates many cellular processes that may interfere with the development and stability of the atherosclerotic plaque. IL-10 is expressed in human atherosclerosis and is associated with decreased signs of inflammation. In the present study, we show that IL-10-deficient C57BL/6J mice fed an atherogenic diet and raised under specific pathogen-free conditions exhibit a significant 3-fold increase in lipid accumulation compared with wild-type mice. Interestingly, the susceptibility of IL-10-deficient mice to atherosclerosis was exceedingly high (30-fold increase) when the mice were housed under conventional conditions. Atherosclerotic lesions of IL-10-deficient mice showed increased T-cell infiltration, abundant interferon-gamma expression, and decreased collagen content. In vivo, transfer of murine IL-10 achieved 60% reduction in lesion size. These results underscore the critical roles of IL-10 in both atherosclerotic lesion formation and stability. Moreover, IL-10 appears to be crucial as a protective factor against the effect of environmental pathogens on atherosclerosis.

Animals↗