Department of Applied Immunology, Nagoya University School of Medicine, Nagoya, Japan.
Biochem Biophys Res Commun. 2010 Jan 8;391(2):1210-5. doi: 10.1016/j.bbrc.2009.12.042. Epub 2009 Dec 16.
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.
已经观察到，即使存在抗移植物抗体，移植物器官仍能继续存活并正常发挥功能。然而，获得这种状态的机制仍不清楚。在这里，我们报告内皮细胞上的抗 HLA 交联诱导 PI3K/AKT 激活，随后通过 Nrf2 介导的抗氧化反应元件 (ARE) 激活诱导抗氧化基因表达。内皮细胞中低浓度抗 HLA 交联激活 PI3K/AKT 可增强对补体攻击的保护作用。实时定量 PCR 和流式细胞术实验表明，转铁蛋白 H 和 HO-1 mRNA 以 PI3K/AKT 依赖性方式诱导，而抗 HLA 交联不增强 CD55 和 CD59 的表达。内皮细胞上的抗 HLA 交联激活转铁蛋白 H ARE，并诱导 Nrf2 在其增强子元件上结合。最后，内皮细胞中 Nrf2 的过表达可减轻补体介导的细胞毒性。这些实验表明，Nrf2 诱导 PI3K/AKT 依赖性细胞保护基因是防止补体攻击的重要机制。因此，激活该途径的方案可能是移植中避免移植物排斥的潜在策略。
