The regulatory T cell effector soluble fibrinogen-like protein 2 induces tubular epithelial cell apoptosis in renal transplantation
The regulatory T cell effector soluble fibrinogen-like protein 2 induces tubular epithelial cell apoptosis in renal transplantation
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调节性T细胞效应可溶性纤维蛋白原样蛋白2诱导肾移植肾小管上皮细胞凋亡
DOI：
10.1177/1535370213514921
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发表时间：
2014-02-01
影响因子：
3.2
通讯作者：
Zhu, Tongyu
中科院分区：
文献类型：
--
作者：
Zhao, Zitong;Yang, Cheng;Zhu, Tongyu
急性排斥反应（AR）阻碍了肾移植物的存活。肾小管上皮细胞（TEC）凋亡导致AR中移植物过早丢失，但其机制尚不清楚。可溶性纤维蛋白原样蛋白2（sFGL 2）是调节性T细胞（Treg）的一种新型效应子，可诱导细胞凋亡，介导组织损伤。我们以前发现，血清sFGL 2显着增加肾移植排斥反应患者。在这项研究中，sFGL 2在AR中的作用进一步在体内和体外研究。检测30例AR或肾功能稳定的肾移植受者血清sFGL 2水平和外周血CD 4 + CD 25 + Foxp 3 + Treg百分比。用sFGL 2、肿瘤坏死因子（TNF）-α或磷酸盐缓冲盐水刺激人TEC，并在体外研究细胞凋亡。进一步评估TEC中凋亡相关基因的表达。本研究获得了复旦大学伦理委员会的批准。我们的研究结果表明，与外周血Treg相关的血清sFGL 2水平在AR患者中显著升高。在体外，sFGL 2可显著诱导TEC凋亡，并上调CASP-3、CASP-8、CASP-9、CASP-10、TRADD、TNFSF 10、FADD、FAS、FASLG、BAK 1、BAD、BAX和NF-KB 1等促凋亡基因表达。然而，在抗凋亡基因的表达中没有观察到显著变化，包括CARD-18、NAIP、BCL 2、IKBKB和TBK 1。因此，sFGL 2作为Treg的效应子，诱导TEC凋亡。我们的研究表明，sFGL 2是一个潜在的调解人在同种异体移植排斥反应的发病机制，并提供了新的见解调节性T细胞在AR的作用。
Acute rejection (AR) hinders renal allograft survival. Tubular epithelial cell (TEC) apoptosis contributes to premature graft loss in AR, while the mechanism remains unclear. Soluble fibrinogen-like protein 2 (sFGL2), a novel effector of regulatory T cells (Treg), induces apoptosis to mediate tissue injury. We previously found that serum sFGL2 significantly increased in renal allograft rejection patients. In this study, the role of sFGL2 in AR was further investigated both in vivo and in vitro. The serum level of sFGL2 and the percentage of CD4+CD25+Foxp3+ Treg in the peripheral blood were measured in renal allograft recipients with AR or stable renal function (n = 30 per group). The human TEC was stimulated with sFGL2, tumor necrosis factor (TNF)-α, or phosphate buffered saline and investigated for apoptosis in vitro. Apoptosis-associated genes expression in TEC was further assessed. Approval for this study was obtained from the Ethics Committee of Fudan University. Our results showed that the serum level of sFGL2, correlated with Treg in the peripheral blood, was significantly increased in the AR patients. In vitro, sFGL2 remarkably induced TEC apoptosis, with a significant up-regulation of proapoptotic genes, including CASP-3, CASP-8, CASP-9, CASP-10, TRADD, TNFSF10, FADD, FAS, FASLG, BAK1, BAD, BAX, and NF-KB1. However, no significant changes were observed in the expression of antiapoptotic genes, including CARD-18, NAIP, BCL2, IKBKB, and TBK1. Therefore, sFGL2, an effector of Treg, induces TEC apoptosis. Our study suggests that sFGL2 is a potential mediator in the pathogenesis of allograft rejection and provides novel insights into the role of Treg in AR.