The peroxisome proliferator-activated receptor gamma ligand rosiglitazone delays the onset of inflammatory bowel disease in mice with interleukin 10 deficiency.
OBJECTIVE
To test whether the peroxisome proliferator-activated receptor gamma (PPARgamma) 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 gamma (IFNgamma), interleukin 17 (IL-17), tumor necrosis factor alpha, and the inducible nitric oxide synthase mRNA in the colon, whereas expression of IL-12p40 was unchanged. PPARgamma was detected in epithelial cells throughout the crypts and surface. Ro increased expression of PPARgamma 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 PPARgamma 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
PPARgamma is expressed, and the PPARgamma 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.
Lytle
Christian
C
Biomedical Sciences Division, Department of Biology, University of California Riverside, Riverside, California 92521-0121, USA.
Tod
Tara J
TJ
Vo
Kathy T
KT
Lee
Jimmy W
JW
Atkinson
Roscoe D
RD
Straus
Daniel S
DS
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006965:Hyperplasia; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000517:prevention & control* / Q000662:veterinary; D016753:Interleukin-10 / Q000172:deficiency*; D008297:Male; D051379:Mice; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
D016207:Cytokines; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D016753:Interleukin-10