Cyclosporine regulates intestinal epithelial apoptosis via TGF-beta-related signaling.

Abstract

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-beta-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-beta 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-beta 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-beta antibody treatment. These results indicated that cyclosporine could have a protective role against epithelial apoptosis associated with upregulation of TGF-beta-related signaling.

• Authors: Yuki Satoh, Yoh Ishiguro, Hirotake Sakuraba, Shogo Kawaguchi, Hiroto Hiraga, Shinsaku Fukuda, Akio Nakane
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 297 Issue 3 Pg. G514-9 (Sep 2009) ISSN: 1522-1547 [Electronic] United States
• PMID: 19608730 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• CASP8 and FADD-Like Apoptosis Regulating Protein
• Immunosuppressive Agents
• Smad2 Protein
• Smad2 protein, mouse
• Transforming Growth Factor beta
• Cyclosporine
• Dextran Sulfate
• Casp8 protein, mouse
• Caspase 8

Topics

• Animals
• Antibodies (pharmacology)
• Apoptosis (drug effects)
• Body Weight
• CASP8 and FADD-Like Apoptosis Regulating Protein (metabolism)
• Caspase 8 (metabolism)
• Colitis (chemically induced, metabolism, pathology, prevention & control)
• Colon (drug effects, metabolism, pathology)
• Cyclosporine (pharmacology)
• Dextran Sulfate
• Disease Models, Animal
• Female
• Immunosuppressive Agents (pharmacology)
• Intestinal Mucosa (drug effects, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Phosphorylation
• Signal Transduction (drug effects)
• Smad2 Protein (metabolism)
• Time Factors
• Transforming Growth Factor beta (immunology, metabolism)
• Up-Regulation