The peroxisome proliferator‐activated receptor γ ligand rosiglitazone delays the onset of inflammatory bowel disease in mice with interleukin 10 deficiency

Aims: To test whether the peroxisome proliferator‐activated receptor γ (PPARγ) ligand rosiglitazone (Ro) has therapeutic activity in the IL‐10−/− mouse model of inflammatory bowel disease (IBD), and to identify the cellular targets and molecular mechanisms of Ro action. Methods: The progression of spontaneous chronic colitis in IL‐10−/− mice was compared in 5‐week‐old mice fed a standard diet with or without Ro for 12 weeks. The possible therapeutic effect of Ro was also tested over a 6‐week interval in older IL‐10−/− mice with established IBD. Results: Treatment with Ro slowed the onset of spontaneous IBD in IL‐10−/− mice. Crypt hyperplasia, caused by increased mitotic activity of crypt epithelial cells, was also delayed by Ro. Treatment with Ro significantly decreased expression of interferon γ (IFNγ), interleukin 17 (IL‐17), tumor necrosis factor α, and the inducible nitric oxide synthase mRNA in the colon, whereas expression of IL‐12p40 was unchanged. PPARγ was detected in epithelial cells throughout the crypts and surface. Ro increased expression of PPARγ protein in these cells, suggesting the existence of a positive feedback loop that would potentiate its action in these cells. Ro also specifically increased expression of a novel PPAR target, aquaporin‐8 (AQP8), in differentiated colonic epithelial surface cells, demonstrating that PPARγ is not only present but also regulates gene expression in these cells in vivo. Finally, Ro was ineffective in improving disease activity in older IL‐10−/− mice with established IBD. Conclusions: PPARγ is expressed, and the PPARγ ligand Ro regulates gene expression in colonic epithelial cells. As a single agent, Ro works best for disease prevention in the IL‐10−/− mouse model for IBD.