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Am J Physiol Gastrointest Liver Physiol 297: G514-G519, 2009. First published July 16, 2009; doi:10.1152/ajpgi.90608.2008
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INFLAMMATION/IMMUNITY/MEDIATORS

Cyclosporine regulates intestinal epithelial apoptosis via TGF-β-related signaling

Yuki Satoh,1 Yoh Ishiguro,1 Hirotake Sakuraba,1 Shogo Kawaguchi,1 Hiroto Hiraga,1 Shinsaku Fukuda,1 and Akio Nakane2

Departments of 1Gastroenterology and Hematology and 2Microbiology and Immunology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

Submitted 23 October 2008 ; accepted in final form 15 July 2009

Cyclosporine is a potent immunomodulator and has a beneficial effect in the treatment of ulcerative colitis (UC). We analyzed the mechanism of the effects of cyclosporine on the regulation of epithelial apoptosis via TGF-β-related signaling, because the balance between the apoptosis and regeneration of epithelial cells seems to be a key factor to maintain the intestinal homeostasis. For this purpose, colitis was induced by treatment of 4% dextran sulfate sodium (DSS), and the effect of treatment with cyclosporine and anti-TGF-β antibody was assessed. Treatment with cyclosporine ameliorated body weight loss, mucosal destruction, and epithelial apoptosis in DSS-induced colitis. Cyclosporine was shown to upregulate the expression of TGF-β in the colonic tissue, enhance the expression of p-Smad2 and cFLIP in epithelial cells, and inhibit caspase-8 activity but not caspase-1 or -9. Upregulation of cFLIP in the colonic epithelial cells, amelioration of body weight loss, and mucosal destruction by cyclosporine were attenuated by anti-TGF-β antibody treatment. These results indicated that cyclosporine could have a protective role against epithelial apoptosis associated with upregulation of TGF-β-related signaling.

caspase-8; dextran sulfate sodium; Smad2; cFLIP; ulcerative colitis


Address for reprint requests and other correspondence: Y. Ishiguro, Dept. of Gastroenterology and Hematology, Hirosaki Univ. Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan (e-mail: yishihki{at}msn.com)






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