Department of Endocrinology and Metabolism, (X.Y., H.T., Ky.K., H.K.O., R.T., Ka.K., T.T.), Life Sciences Division, Engineering and Technology Department (H.T.), and Department of Integrative Medicine for Longevity (K.-A.I.), Graduate School of Medical Sciences, Kanazawa University, Kanazawa City, Ishikawa Prefecture, Japan.
Department of Endocrinology and Metabolism, (X.Y., H.T., Ky.K., H.K.O., R.T., Ka.K., T.T.), Life Sciences Division, Engineering and Technology Department (H.T.), and Department of Integrative Medicine for Longevity (K.-A.I.), Graduate School of Medical Sciences, Kanazawa University, Kanazawa City, Ishikawa Prefecture, Japan
J Pharmacol Exp Ther. 2022 Aug;382(2):199-207. doi: 10.1124/jpet.121.001175.
Cyclosporine A (CsA) is an immunosuppressant applied worldwide for preventing graft rejection and autoimmune diseases. However, CsA elevates oxidative stress, which can lead to liver injuries. The present study aimed to clarify the mechanisms underlying the CsA-mediated oxidative stress. Among the redox proteins, CsA concentration-dependently downregulated -encoding selenoprotein P, a major circulating antioxidant protein reducing reactive oxygen species, in hepatocytes cell lines and primary hepatocytes. The luciferase assay identified the CsA-responsive element in the promoter containing a putative binding site for forkhead box protein O (FoxO) 1. The CsA-mediated suppression on the promoter was independent of the nuclear factor of activated T-cell, a classic target repressed by CsA. A chromatin immunoprecipitation assay showed that CsA suppressed the FoxO1 binding to the promoter. knockdown significantly downregulated expression in H4IIEC3 cells. Furthermore, CsA downregulated FoxO1 by inactivating its upstream signal transducer and activator of transcription 3 (STAT3). Knockdown of downregulated and expression in hepatocytes. These findings revealed a novel mechanism underlying CsA-induced oxidative stress by downregulating the STAT3-FoxO1- pathway in hepatocytes. SIGNIFICANCE STATEMENT: This study shows that Cyclosporine A (CsA) downregulates , an antioxidant protein, by suppressing the signal transducer and activator of transcription 3-forkhead box protein O1 pathway in hepatocytes, possibly one of the causations of CsA-induced oxidative stress in hepatocytes. The present study sheds light on the previously unrecognized CsA-redox axis.
环孢素 A（CsA）是一种在全球范围内用于预防移植物排斥和自身免疫性疾病的免疫抑制剂。然而，CsA 会引起氧化应激，从而导致肝脏损伤。本研究旨在阐明 CsA 介导的氧化应激的机制。在氧化还原蛋白中，CsA 浓度依赖性地下调编码硒蛋白 P 的基因，硒蛋白 P 是一种主要的循环抗氧化蛋白，可减少活性氧。在肝细胞系和原代肝细胞中。荧光素酶测定鉴定出包含叉头框蛋白 O（FoxO）1 可能结合位点的 启动子中的 CsA 反应元件。CsA 对 启动子的抑制作用不依赖于 T 细胞激活核因子，这是 CsA 经典的靶标。染色质免疫沉淀试验表明，CsA 抑制 FoxO1 与 启动子的结合。 敲低显着下调 H4IIEC3 细胞中的 表达。此外，CsA 通过使上游信号转导和转录激活因子 3（STAT3）失活来下调 FoxO1。 敲低显着下调肝细胞中的 表达。这些发现揭示了 CsA 在肝细胞中诱导氧化应激的新机制，即通过下调 STAT3-FoxO1-通路。 意义陈述：本研究表明，环孢素 A（CsA）通过抑制信号转导和转录激活因子 3-叉头框蛋白 O1 通路下调抗氧化蛋白 ，这可能是 CsA 诱导肝细胞氧化应激的原因之一。本研究揭示了以前未被认识到的 CsA-氧化还原轴。
