PPAR and PPAR negatively regulate specific subsets of lipopolysaccharide and IFN- target genes in macrophages

Natural and synthetic agonists of the peroxisome proliferatoractivated receptor (PPAR ) regulate adipocyte differentiation, glucose homeostasis, and inflammatory responses. Although effects on adipogenesis and glucose metabolism are genetically linked to PPAR , the PPAR dependence of antiinflammatory responses of these substances is less clear. Here, we have used a combination of mRNA expression profiling and conditional disruption of the PPAR gene in mice to characterize programs of transcriptional activation and repression by PPAR agonists in elicited peritoneal macrophages. Natural and synthetic PPAR agonists, including the thiazolidinedione rosiglitazone (Ro), modestly induced the expression of a surprisingly small number of genes, several of which were also induced by a specific PPAR agonist. The majority of these genes encode proteins involved in lipid homeostasis. In contrast, Ro inhibited induction of broad subsets of lipopolysaccharide and IFNtarget genes in a genespecific and PPAR -dependent manner. At high concentrations, Ro inhibited induction of lipopolysaccharide target genes in PPAR deficient macrophages, at least in part by activating PPAR . These studies establish overlapping transactivation and transrepression functions of PPAR and PPAR in macrophages and suggest that a major transcriptional role of PPAR is negative regulation of specific subsets of genes that are activated by T helper 1 cytokines and pathogenic molecules that signal through pattern recognition receptors. These findings support a physiological role of PPAR in regulating both native and acquired immune responses.