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.
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INSERM U325, Département d'Athérosclérose, Institut Pasteur de Lille, 1 rue Pr. Calmette 59019 Lille and Faculté de Pharmacie, Université de Lille II, 59000 Lille, France.
Gervois
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Fruchart
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Staels
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D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D020672:I-kappa B Proteins; D007249:Inflammation / Q000503:physiopathology*; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000072000:NF-KappaB Inhibitor alpha