Inhibitory effect of intestinal epithelial necroptosis via FLIP by cyclosporine

• Project/Area Number: 17K09367
• 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, 准教授 (90422063)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 腸上皮ネクロプトーシス / シクロスポリン / ネクロプトーシス / HMGB-1 / 腸上皮細胞 / 炎症性腸疾患

Outline of Final Research Achievements

We assessed the expression of molecules which adjusted necroptosis by cyclosporine in DSS-induced colitis model.As for the expression of RIPK3, AMPK ,MLKL and RIPK1, there was no defferences it between the control group and the cyclosporine-treated group.Whereas the expression of HMGB-1, which was one of inflammatory mediators from necroptosis, was significantly inhibited by cyclosporine as compared with controls.
Our data suggested that cyclosporine inihibited the expression of HMGB1 independent of RIPK3, AMPK which were conventional reguratory molecules of necroptosis.

Academic Significance and Societal Importance of the Research Achievements

シクロスポリンによるネクロプトーシス実行メディエーターであるHMGB-1の発現調節効果の存在が明らかになった。従来のネクロプトーシス調節分子を介さない機序が存在する可能性があり、腸上皮ネクロプトーシスの新しいメカニズムあるいはHMGB1の治療マーカーの可能性など、さらなる解析を進める意義があると考えられる。