Attenuation of experimental colonic injury by thiazolidinedione agents

Objective: We investigated the potential use and action mechanisms of thiazolidin-gamma, namely pioglitazone and netoglitazone, during dextran sulfate sodium (DSS)-induced colitis in mice. Methods: Colitis was induced by the drinking of 2.5% DSS for 7 days. In the prophylactic protocol, pioglitazone or netoglitazone was administered 2 days before the first DSS exposure and repeated daily for a total of 10 doses. In the therapeutic protocol, pioglitazone was administered 2 days after the first DSS exposure and repeated daily for a total of 10 doses. The effect of pioglitazone on proinflammatory cytokine signaling was examined both in vivo and in vitro. Results: Colitis was significantly attenuated by both pioglitazone and netoglitazone in the prophylactic protocol and by pioglitazone in the therapeutic protocol. The improvement of colitis by pioglitazone was associated with decreased colonic interleukin-6, and phospho-signal transducer and activator of transcription-3 levels. In vitro experiments revealed that culturing lamina propria mononuclear cells in the presence of pioglitazone down-regulated the production of interleukin-6. Conclusions: These TZD agents should be considered for use as new therapeutic agents in intestinal inflammation such as inflammatory bowel disease. TZD-induced improvement in inflammation is explained, in part, by down-regulation of proinflammatory cytokine signaling.