The Interleukin-1 receptor antagonist is a direct target gene of PPARalpha in liver

Background/Aims: The Peroxisome Proliferator-Activated Receptor (PPAR) alpha belongs to the superfamily of Nuclear Receptors and plays an important role in numerous cellular processes, including lipid metabolism. It is known that PPAR alpha also has an anti-inflammatory effect, which is mainly achieved by down-regulating pro-inflammatory genes. The objective of this study was to further characterize the role of PPARa in inflammatory gene regulation in liver. Results: According to Affymetrix micro-array analysis, the expression of various inflammatory genes in liver was decreased by treatment of mice with the synthetic PPAR alpha( agonist Wy14643 in a PPAR alpha-dependent manner. In contrast, expression of Interleukin-1 receptor antagonist (IL-1ra), which was acutely stimulated by LPS treatment, was induced by PPAR alpha. Up-regulation of IL-1ra by LPS was lower in PPAR alpha -/- mice compared to Wt mice. Transactivation and chromatin immunoprecipitation studies identified IL-Ira as a direct positive target gene of PPAR alpha with a functional PPRE present in the promoter. Up-regulation of IL-1ra by PPARa was conserved in human HepG2 hepatoma cells and the human monocyte/macrophage THP-1 cell line. Conclusions: In addition to down-regulating expression of pro-inflammatory genes, PPARa suppresses the inflammatory response by direct up-regulation of genes with anti-inflammatory properties. (C) 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved