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 transcription factors that is predominantly expressed in adipose tissue, adrenal gland and spleen. PPAR-gamma has been demonstrated to regulate adipocyte differentiation and glucose homeostasis in response to several structurally distinct compounds, including thiazolidinediones and fibrates. Naturally occurring compounds such as fatty acids and the prostaglandin D2 metabolite 15-deoxy-delta prostaglandin J2 (15d-PGJ2) bind to PPAR-gamma and stimulate transcription of target genes. Prostaglandin D2 metabolites have not yet been identified in adipose tissue, but are major products of arachidonic-acid metabolism in macrophages, 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-PGJ2 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-kappaB. These observations suggest that PPAR-gamma and locally produced prostaglandin D2 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.
Ricote
M
M
Department of Medicine, University of California, San Diego, La Jolla 92093-0651, USA.
Li
A C
AC
Willson
T M
TM
Kelly
C J
CJ
Glass
C K
CK
D001854:Bone Marrow Cells / Q000502:physiology; D017364:Collagenases / Q000096:biosynthesis; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D008262:Macrophage Activation / Q000502:physiology*; D008264:Macrophages / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000502:physiology; D020780:Matrix Metalloproteinase 9; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D018836:Inflammation Mediators; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D019001:Nitric Oxide Synthase; D017364:Collagenases; D020780:Matrix Metalloproteinase 9; D015230:Prostaglandin D2