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

Philippe Delerive, Karolien De Bosscher, Sandrine Besnard, Wim Vanden Berghe, Jeffrey M. Peters, Frank J. Gonzalez, Jean Charles Fruchart, Alain Tedgui, Guy Haegeman, Bart Staels

Research output: Contribution to journalArticle

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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 α (PPARα) 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 PPARα-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 PPARα wild-type, but not of PPARα-null mice, demonstrating a role for PPARα in this fibrate action. In human aortic SMC, fibrates inhibit IL-1-induced IL-6 gene expression. Furthermore, activation of PPARα represses both c-Jun- and p65-induced transcription of the human IL-6 promoter. Transcriptional interference between PPARα and both c-Jun and p65 occurs reciprocally, since c-Jun and p65 also inhibit PPARα-mediated activation of a PPAR response element-driven promoter. This transcriptional interference occurs independent of the promoter context as demonstrated by cotransfection experiments using PPARα, p65, and c-Jun Ga14 chimeras. Overexpression of the transcriptional coactivator cAMP-responsive element- binding protein-binding protein (CBP) does not relieve PPARα-mediated transcriptional repression of p65 and c-Jun. Finally, glutathione S- transferase pull-down experiments demonstrate that PPARα physically interacts with c-Jun, p65, and CBP. Altogether these data indicate that fibrates inhibit the vascular inflammatory response via PPARα by interfering with the NF-κB and AP-1 transactivation capacity involving direct protein- protein interaction with p65 and c-Jun.

Original languageEnglish (US)
Pages (from-to)32048-32054
Number of pages7
JournalJournal of Biological Chemistry
Volume274
Issue number45
DOIs
StatePublished - Nov 5 1999

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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