Cyclosporine protects from apoptosis-mediated epithelial damage through epithelial STAT3 signaling pathway

Research Project

Project/Area Number	26460957
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Gastroenterology
Research Institution	Hirosaki University
Principal Investigator	SAKURABA HIROTAKE 弘前大学, 医学研究科, 講師 (90422063)
Research Collaborator	HIRAGA Hiroto 弘前大学, 大学院医学研究科, 助教 (80637546)
Project Period (FY)	2014-04-01 – 2018-03-31
Project Status	Completed (Fiscal Year 2017)
Budget Amount *help	¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000) Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000) Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000) Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords	炎症性腸疾患 / IL-22受容体 / TGF-beta / シクロスポリン / 腸上皮細胞 / アポトーシス / 腸管上皮細胞 / 腸上皮アポトーシス / TGF-β / STAT-3 / STAT3
Outline of Final Research Achievements	Treatment of cyclosporine ameliorated mucosal destruction through reduction of epithelial apoptosis in DSS-induced colitis model. IL-22 receptor expression and STAT3 phosphorylation in purified intestinal epithelial cells (IECs) were up-regulated in cyclosporine but not in vehicle treated mice. Anti-TGF-beta mAb treatment diminished the protective effect of cyclosporine. In addition, anti-TGF-beta mAb treatment diminished up-regulated IL-22 receptor expression and STAT3 phosphorylation in IECs. In Caco2 cells, the treatment with both cyclosporine and recombinant TGF-beta increased IL-22 receptor expression. These results demonstrate that treatment of cyclosporine can ameliorate apoptosis-mediated epithelial damage through epithelial IL-22 receptor-STAT3 signaling pathway, which required the TGF-beta stimulation.