Induction of I kappa B alpha expression as a mechanism contributing to theanti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators

Chronic inflammation is a hallmark of degenerative diseases such as atheros clerosis. Peroxisome proliferator-activated receptors (PPARs) are transcrip tion factors belonging to the nuclear receptor superfamily, which are expre ssed in the cells of the atherosclerosic lesion PPAR alpha ligands have bee n reported to exert anti-inflammatory activities in different cell types by antagonizing the transcriptional activity of NF-kappaB. In the present stu dy, the influence of PPAR alpha activators on the NF-kappaB signaling pathw ay was investigated. Our results show that fibrates, synthetic PPAR alpha a ctivators, 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 ka ppaB alpha: were affected. Using PPAR alpha -null mice, we demonstrated tha t fibrates induced I kappaB alpha in liver in vivo and that this action req uired PPAR alpha. Furthermore, fibrate treatment induced I kappaB alpha pro tein expression in the cytoplasm and also enhanced IL-1 beta induced accumu lation 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 DN A 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 p otential use in the treatment of inflammatory diseases.