title: Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1.
abstract: 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.
authors.affiliation: INSERM U325, Département d'Athérosclérose, Institut Pasteur de Lille, 1 rue Pr. Calmette 59019 Lille, France.
authors.forename: P
authors.initials: P
authors.lastname: Delerive
authors.forename: K
authors.initials: K
authors.lastname: De Bosscher
authors.forename: S
authors.initials: S
authors.lastname: Besnard
authors.forename: W
authors.initials: W
authors.lastname: Vanden Berghe
authors.forename: J M
authors.initials: JM
authors.lastname: Peters
authors.forename: F J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: J C
authors.initials: JC
authors.lastname: Fruchart
authors.forename: A
authors.initials: A
authors.lastname: Tedgui
authors.forename: G
authors.initials: G
authors.lastname: Haegeman
authors.forename: B
authors.initials: B
authors.lastname: Staels
mesh_terms: D000818:Animals; D019556:COS Cells; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000502:physiology*; D010689:Phlebitis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018808:Transcription Factor AP-1; D014157:Transcription Factors