TY - JOUR
T1 - Peroxisome proliferator-activated receptor α negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-κB and AP-1
AU - Delerive, Philippe
AU - De Bosscher, Karolien
AU - Besnard, Sandrine
AU - Vanden Berghe, Wim
AU - Peters, Jeffrey M.
AU - Gonzalez, Frank J.
AU - Fruchart, Jean Charles
AU - Tedgui, Alain
AU - Haegeman, Guy
AU - Staels, Bart
PY - 1999/11/5
Y1 - 1999/11/5
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.274.45.32048
DO - 10.1074/jbc.274.45.32048
M3 - Article
C2 - 10542237
AN - SCOPUS:0033527569
VL - 274
SP - 32048
EP - 32054
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 45
ER -