Significance of HLA class I antibody-induced antioxidant gene expression for endothelial cell protection against complement attack
Significance of HLA class I antibody-induced antioxidant gene expression for endothelial cell protection against complement attack
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DOI：
10.1016/j.bbrc.2009.12.042
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发表时间：
2010-01-08
影响因子：
3.1
通讯作者：
Kobayashi, Takaaki
中科院分区：
文献类型：
--
作者：
Iwasaki, Kenta;Miwa, Yuko;Kobayashi, Takaaki
已经观察到，即使在抗移植物抗体存在下，移植器官也继续存活并正常发挥功能。然而，获得这种情况背后的机制仍然未知。在这里，我们报告，抗HLA连接内皮细胞诱导PI 3 K/AKT激活，然后通过Nrf 2介导的抗氧化反应元件（ARE）激活抗氧化基因诱导。通过低浓度抗HLA连接激活内皮细胞中的PI 3 K/AKT增强了对补体攻击的保护。实时定量PCR和流式细胞术实验表明，铁蛋白H和HO-1的mRNA诱导PI 3 K/AKT依赖的方式，而CD 55和CD 59的表达没有增强抗HLA连接。内皮细胞上的抗HLA连接激活铁蛋白HARE并诱导其增强子元件上的Nrf 2结合。最后，内皮细胞中Nrf 2的过表达减弱补体介导的细胞毒性。这些实验表明，Nrf 2诱导PI 3 K/AKT依赖性细胞保护基因是防止补体攻击的重要机制。因此，激活该通路的方案将是避免移植物排斥反应的潜在策略。(C)2009 Elsevier Inc. All rights reserved.
It has been observed that a graft organ continues to survive and function normally even in the presence of anti-graft antibodies. However, the mechanisms behind acquirement of this condition remain unknown. Here we report that the anti-HLA ligation on endothelial cells induces PI3K/AKT activation followed by antioxidant gene induction through Nrf2-mediated antioxidant-responsive element (ARE) activation. Activation of PI3K/AKT in endothelial cells by a low concentration of anti-HLA ligation enhances protection from complement attack. A real-time quantitative PCR and flow-cytometry experiment showed that ferritin H and HO-1 mRNAs were induced in a PI3K/AKT-dependent manner, while CD55 and CD59 expression were not enhanced by anti-HLA ligation. Anti-HLA ligation on endothelial cells activates ferritin H ARE and induces Nrf2 binding on its enhancer element. Finally, overexpression of Nrf2 in endothelial cells attenuates complement-mediated cytotoxicity. These experiments suggest that induction of PI3K/AKT-dependent cytoprotective genes by Nrf2 is an important mechanism to prevent complement attack. Thus, a protocol to activate this pathway would be a potential strategy for avoidance of graft rejection in transplantation. (C) 2009 Elsevier Inc. All rights reserved.