1. Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA
2. Divisions of Cellular and Molecular Medicine, and Endocrinology and Metabolism San Diego Veterans Affairs Medical Center, La Jolla, California 92161, USA
3. Division of Cardiology, San Diego Veterans Affairs Medical Center, La Jolla, California 92161, USA
4. Division of Nephrology and the San Diego Veterans Affairs Medical Center, La Jolla, California 92161, USA
5. Department of Medicinal Chemistry, Glaxo Wellcome Research and Development, PO Box 13398, Research Triangle Park, North Carolina 27709, USA

Correspondence to: Correspondence and requests for materials should be addressed to C.K.G. (e-mail: Email: cglass@ucsd.edu).

The peroxisome proliferator-activated receptor- (PPAR-) 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- 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 D₂ metabolite 15-deoxy-^12,14prostaglandin J₂ (15d-PGJ₂) bind to PPAR- and stimulate transcription of target genes^{7, 8, 9, 10}. Prostaglandin D₂metabolites have not yet been identified in adipose tissue, butaremajor products of arachidonic-acid metabolism in macrophages¹¹, raising the possibility that they might serve as endogenous PPAR- ligands in this cell type. Here we show that PPAR- 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-PGJ₂ and synthetic PPAR- ligands. PPAR- inhibits gene expression in part by antagonizing the activities of the transcription factors AP-1, STAT and NF-B. These observations suggest that PPAR- and locally produced prostaglandin D₂ metabolites are involved in the regulation of inflammatory responses, and raise the possibility that synthetic PPAR- ligands may be of therapeutic value in human diseases such as atherosclerosis and rheumatoid arthritis in which activated macrophages exert pathogenic effects.