IRF-1 promotes liver transplant ischemia/reperfusion injury via hepatocyte IL-15/IL-15Rα production.
IRF-1 promotes liver transplant ischemia/reperfusion injury via hepatocyte IL-15/IL-15Rα production.
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DOI：
10.4049/jimmunol.1402505
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发表时间：
2015-06-15
期刊：
影响因子：
--
通讯作者：
Geller DA
中科院分区：
文献类型：
--
作者：
Yokota S;Yoshida O;Dou L;Spadaro AV;Isse K;Ross MA;Stolz DB;Kimura S;Du Q;Demetris AJ;Thomson AW;Geller DA
肝移植(LTX)后的缺血再灌注(I/R)损伤是影响临床预后的重要问题。干扰素调节因子-1(IRF-1)是一种核转录因子，在肝损伤中发挥重要作用。我们的目的是确定IRF-1在同种异体LTX所致的I/R损伤中的免疫调节作用。人和小鼠肝移植再灌流后即刻均可表达IRF-1。IRF-1在I/R损伤中起重要作用，因为通过血清丙氨酸氨基转移酶(ALT)和组织学评估，IRF-1 KO移植物的损伤要小得多。体外实验中，IRF-1可调节小鼠肝细胞和肝树突状细胞(DC)中IL-15的组成性和诱导性表达，以及IL-15Rα的表达。人原代肝细胞中IRF-1的特异性敲除也得到了类似的结果。此外，我们还发现肝细胞是肝脏中产生可溶性IL-15/IL-15Rα复合体的主要细胞。RIL-15/IL-15Rα可显著降低肝移植受者的NK、NKT和CD8+T细胞数量，恢复这些免疫细胞，增强细胞毒效应分子，促进全身炎症反应，加重肝损伤。这些结果表明，IRF-1通过肝细胞IL-15/IL-15Rα的产生促进LTX的I/R损伤，提示靶向IRF-1和IL-15/IL-15Rα可能在减轻LTX所致的I/R损伤方面有效。
Ischemia and reperfusion (I/R) injury following liver transplantation (LTx) is an important problem that significantly impacts clinical outcomes. Interferon regulatory factor-1 (IRF-1) is a nuclear transcription factor that plays a critical role in liver injury. Our objective was to determine the immunomodulatory role of IRF-1 during I/R injury following allogeneic LTx. IRF-1 was induced in liver grafts immediately after reperfusion in both human and mouse LTx. IRF-1 contributed significantly to I/R injury as IRF-1 KO grafts displayed much less damage assessed by serum alanine aminotransferase (ALT) and histology. In vitro, IRF-1 regulated both constitutive and induced expression of IL-15, as well as IL-15Rα mRNA expression in murine hepatocytes and liver dendritic cells (DC). Specific knockdown of IRF-1 in human primary hepatocytes gave similar results. In addition, we identified hepatocytes as the major producer of soluble IL-15/IL-15Rα complexes in the liver. IRF-1 KO livers had significantly reduced NK, NKT and CD8+T cell numbers, while rIL-15/IL-15Rα restored these immune cells, augmented cytotoxic effector molecules, promoted systemic inflammatory responses, and exacerbated liver injury in IRF-1 KO graft recipients. These results indicate that IRF-1 promotes LTx I/R injury via hepatocyte IL-15/IL-15Rα production and suggest that targeting IRF-1 and IL-15/IL-15Rα may be effective in reducing I/R injury associated with LTx.
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影响因子：
5.5
作者：
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