THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA 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 transc ription factors that is predominantly expressed in adipose tissue, adr enal gland and spleen(1-3). PPAR-gamma has been demonstrated to regula te adipocyte differentiation and glucose homeostasis in response to se veral structurally distinct compounds, including thiazolidinediones an d 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 ta rget genes(7-10). Prostaglandin D-2 metabolites have not yet been iden tified in adipose tissue, but are major products of arachidonic-acid m etabolism 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, gelati nase B and scavenger receptor A genes in response to 15d-PGJ(2) and sy nthetic PPAR-gamma ligands, PPAR-gamma inhibits gene expression in par t by antagonizing the activities of the transcription factors AP-1, ST AT and NF-kappa B, These observations suggest that PPAR-gamma and loca lly produced prostaglandin D-2 metabolites are involved in the regulat ion of inflammatory responses, and raise the possibility that syntheti c PPAR-gamma ligands may be of therapeutic value in human diseases suc h as atherosclerosis and rheumatoid arthritis in which activated macro phages exert pathogenic effects.