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

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