PPAR-gamma dependent and independent effects on macrophage-gene expressionin lipid metabolism and inflammation

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is highly exp ressed in lipid-accumulating macrophages of the coronary artery. In light o f this, the wide-spread clinical use of thiazolidinediones (TZDs) in the tr eatment of type II diabetes raises concerns about the role of PPAR-gamma in macrophage function and disease progression. To define the role of PPAR-ga mma in macrophage biology, we used homologous recombination to create embry onic stem cells that were homozygous for a null mutation in the PPAR-gamma gene. We demonstrate here that PPAR-gamma is neither essential for nor subs tantially affects the development of the macrophage lineage both in vitro a nd in vivo. In contrast, we show it is an important regulator of the scaven ger receptor CD36, which has been genetically linked to lipid accumulation in macrophages. Both 15-deoxy-Delta (12,14)prostaglandin J(2) and thiazolid inediones have anti-inflammatory effects that are independent of PPAR-gamma . We show that PPAR-gamma is required for positive effects of its ligands i n modulating macrophage lipid metabolism, but that inhibitory effects on cy tokine production and inflammation may be receptor independent.