PPAR-gamma in inflammation.

The ligand-dependent transcription factor, peroxisome proliferator activated receptor, (PPAR-gamma), is a member of the nuclear hormone receptor superfamily and a target of antidiabetic thiazolidinediones (TZDs). Initially characterized for its effects in glucose and lipid metabolism, PPAR-gamma activation has been shown to play critical roles in the inhibition of inflammatory vascular diseases such as atherosclerosis. Since PPAR-gamma agonists have receptor-independent actions, knockout studies are required to determine whether PPAR-gamma is necessary for the inhibitory effects of the PPAR-gamma agonists. Due to the pleiotropic effects of the PPAR-gamma activation, establishing which cell types are responsible for the anti-inflammatory effects observed in whole organism studies is difficult without the use of the cell-specific knockouts. To unravel the complex role of PPAR-gamma in inflammation and to begin categorizing relative contributions of PPAR-gamma activity in different cell types, we created two PPAR-gamma knockout models: pancreatic epithelial cell knockout and vascular endothelial cell knockout. These knockout models not only provided insight into the important role PPAR-gamma plays in the control of cell inflammation but also showed that TZDs act directly through PPAR-gamma in suppressing inflammation in an in vivo model of acute pancreatitis and in an in vitro models of endothelial cell inflammation. We show that PPAR-gamma in acinar cells, and not in inflammatory cells, is the target of the TZD anti-inflammatory activity in the model of acute pancreatitis. In vascular endothelial cells, PPAR-gamma is required for TZD activity and PPAR-gamma activation inhibits the function of a pro-inflammatory transcription factor NF-kappaB by decreasing the formation of functional transcriptional complexes at the promoters of NF-kappaB target genes.Ph.D.Biological SciencesMolecular biologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/126726/2/3276192.pd