The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation

The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors that is predominantly expressed in adipose tissue, adrenal gland and spleen 1 , 2 , 3 . PPAR-γ has been demonstrated to regulate adipocyte differentiation and glucose homeostasis in response to several structurally distinct compounds, including thiazolidinediones and fibrates 3 , 4 , 5 , 6 . Naturally occurring compounds such as fatty acids and the prostaglandin D 2 metabolite 15-deoxy-Δ 12,14 prostaglandin J 2 (15d-PGJ 2 ) bind to PPAR-γ and stimulate transcription of target genes 7 , 8 , 9 , 10 . Prostaglandin D 2 metabolites have not yet been identified in adipose tissue, butaremajor products of arachidonic-acid metabolism in macrophages 11 , raising the possibility that they might serve as endogenous PPAR-γ ligands in this cell type. Here we show that PPAR-γ is markedly upregulated in activated macrophages and inhibits the expression of the inducible nitric oxide synthase, gelatinase B and scavenger receptor A genes in response to 15d-PGJ 2 and synthetic PPAR-γ ligands. PPAR-γ inhibits gene expression in part by antagonizing the activities of the transcription factors AP-1, STAT and NF-κB. These observations suggest that PPAR-γ and locally produced prostaglandin D 2 metabolites are involved in the regulation of inflammatory responses, and raise the possibility that synthetic PPAR-γ ligands may be of therapeutic value in human diseases such as atherosclerosis and rheumatoid arthritis in which activated macrophages exert pathogenic effects.