Induction of IκBα expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-α 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 PPAR alpha 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 PPAR alpha activators on the NF-kappaB signaling pathway was investigated. Our results show that fibrates, synthetic PPAR alpha activators, induced the expression of the inhibitory protein I kappaB alpha in human aortic smooth muscle cells as well as in primary human hepatocytes, whereas neither I kappaB-kinase activity nor the degradation rate of I kappaB alpha: were affected. Using PPAR alpha -null mice, we demonstrated that fibrates induced I kappaB alpha in liver in vivo and that this action required PPAR alpha. Furthermore, fibrate treatment induced I kappaB alpha protein expression in the cytoplasm and also enhanced IL-1 beta induced accumulation of I kappaB alpha protein in the nucleus. These actions of fibrates on I kappaB alpha 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 PPAR alpha agonists and reinforce their potential use in the treatment of inflammatory diseases.