A novel PPARγ gene therapy to control inflammation associated with inflammatory bowel disease in a murine model

Peroxisome proliferator-activated receptor γ (PPARγ) is one of the nuclear receptors that plays a central role in adipocyte differentiation and insulin sensitivity. PPARγ has also recently been recognized as an endogenous regulator of intestinal inflammation. However, its levels are decreased during chronic inflammation in human and mice, thus limiting PPARγ ligand therapy during established disease. We sought to determine whether this decrease in PPARγ could be counteracted by a gene therapy approach. We characterized PPARγ levels in experimental colitis associated with dextran sodium sulfate administration to mice. In this model, the therapeutic benefits of PPARγ gene therapy using a replication-deficient adenovirus vector expressing PPARγ (Ad-PPARγ) was assessed. PPARγ protein levels were decreased in whole colonic tissue, lamina propria lymphocytes, and peritoneal exudate cells during the course of colitis. PPARγ gene delivery using Ad-PPARγ restored responsiveness to a PPARγ ligand, resulting in marked amelioration of tissue inflammation associated with the colitis, which included attenuation of intercellular adhesion molecule-1, cyclooxygenase-2 and tumor necrosis factor-α expression. Our results suggest that gene delivery of PPARγ can be used to restore and/or enhance endogenous anti-inflammatory processes that are normally operative in mammalian tissues such as in the colon.