The effect of immunosuppressant FK506 on hepatic function of graft

免疫抑制剂FK506对移植物肝功能的影响

• 批准号: 14571243
• 负责人: KAMIYAMA Yasuo
• 金额: $ 2.18万
• 依托单位: Kansai Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571243/
• 关键词: FK506; Cyclosporin A; Inducible nitric oxide synthase; Interleukin 1; Nuclear factor-kappa B; Rat cultured hepatocytes; cytokine-induced neutrophil chemoattractant; ラット初代肝細胞培養; 低酸素障害; ケトン体比; Heat shock protein

Studies were performed to determine whether the immunosuppressants FK506 and cyclosporin A directly influence gene expression of inducible nitric oxide synthase by IL-1β in hepatocytes. Methods : Primary cultures of rat hepatocytes were treated with IL-1β in the presence and absence of FK506 or cyclosporin A. Release of nitrite into culture medium, levels of inducible nitric oxide synthase protein and mRNA, and activation of NF-κB were compared with the two drugs. Results : IL-1β increased levels of inducible nitric oxide synthase protein and inducible nitric oxide synthase mRNA, as well as nitric oxide production, in the cultured hepatocytes. NF-κB, an important transcription factor in inducible nitric oxide synthase gene expression in response to inflammation, also appeared in the nuclear fraction of hepatocytes after addition of IL-1β. FK506 markedly inhibited the nitric oxide formation, inducible nitric oxide synthase protein synthesis and inducible nitric oxide synthase mRNA expression induced by IL-1β, but cyclosporin A had no effects. Furthermore, FK506 inhibited NF-κB activation and decreased mRNA levels of the p50/p65 subunits of NF-κB. Conclusions : These results demonstrate that FK506, but not cyclosporin A, inhibits the induction of inducible nitric oxide synthase expression during NF-κB activation

研究了免疫抑制剂FK 506和环孢素A是否直接影响IL-1β诱导的肝细胞一氧化氮合酶基因表达。方法：原代培养的大鼠肝细胞经IL-1β处理后，加入或不加入FK 506或环孢菌素A。比较两种药物在培养液中亚硝酸盐的释放、诱导型一氧化氮合酶蛋白和mRNA水平以及NF-κB的活化。结果如下：IL-1β可增加培养肝细胞中诱导型一氧化氮合酶蛋白和诱导型一氧化氮合酶mRNA的水平，以及一氧化氮的产生。NF-κB是炎症反应诱导型一氧化氮合酶基因表达的重要转录因子，加入IL-1β后，NF-κ B也出现在肝细胞核部分。FK 506可显著抑制IL-1β诱导的NO生成、诱导型一氧化氮合酶蛋白合成及诱导型一氧化氮合酶mRNA表达，而环孢素A无此作用。此外，FK 506还可抑制NF-κB的活化，并降低NF-κB的p50/p65亚基的mRNA水平。结论：这些结果表明，在NF-κB活化过程中，FK 506而不是环孢菌素A抑制诱导型一氧化氮合酶表达的诱导