Peroxisome proliferator-activated receptor α negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-κB 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 (PPAR alpha) 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 PPAR alpha-null mice display an exacerbated response to inflammatory stimuli, such as li popolysaccharide (LPS), as demonstrated by increased IL-6 secretion. Furthermore, fibrate treatment represses IL-6 mRNA levels in LPS-stimulated aortas of PPAR alpha wild-type, but not of PPAR alpha-null mice, demonstrating a role for PPAR alpha in this fibrate action. in human aortic SMC, fibrates inhibit IL-1-induced IL-6 gene expression. Furthermore, activation of PPAR alpha represses both c-Jun- and p65-induced transcription of the human IL-6 promoter. Transcriptional interference between PPAR alpha and both c-Jun and p65 occurs reciprocally, since c-Jun and p65 also inhibit PPAR alpha-mediated activation of a PPAR response element-driven promoter. This transcriptional interference occurs independent of the promoter context as demonstrated by cotransfection experiments using PPAR alpha, p65, and c-Jun Gal4 chimeras. Overexpression of the transcriptional coactivator cAMP-responsive element-binding protein-binding protein (CBP) does not relieve PPAR alpha-mediated transcriptional repression of p65 and c-Jun, Finally, glutathione S-transferase pull-down experiments demonstrate that PPAR alpha physically interacts with c-dun, p65, and CBP. Altogether these data indicate that fibrates inhibit the vascular inflammatory response via PPAR alpha by interfering with the NF-kappa B and AP-1 transactivation capacity involving direct protein-protein interaction with p65 and c-Jun.