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

Background & Aims: Peroxisome proliferator-activated receptor gamma (PPARgamma) is one of the nuclear receptors that plays a central role in adipocyte differentiation and insulin sensitivity. PPARgamma 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 PPARgamma ligand therapy during established disease. We sought to determine whether this decrease in PPARgamma could be counteracted by a gene therapy approach. Methods: We characterized PPARgamma levels in experimental colitis associated with dextran sodium sulfate administration to mice. In this model, the therapeutic benefits of PPARgamma gene therapy using a replication-deficient adenovirus vector expressing PPARgamma (Ad-PPARgamma) was assessed. Results: PPARgamma protein levels were decreased in whole colonic tissue, lamina propria lymphocytes, and peritoneal exudate cells during the course of colitis. PPARgamma gene delivery using Ad-PPARgamma restored responsiveness to a PPARgamma 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-alpha expression. Conclusions: Our results suggest that gene delivery of PPARgamma can be used to restore and/or enhance endogenous anti-inflammatory processes that are normally operative in mammalian tissues such as in the colon.