a Institute of Radiation Medicine, Fudan University, Shanghai 200032, China; and.
Radiat Res. 2014 Jul;182(1):111-21. doi: 10.1667/RR13736.1. Epub 2014 Jun 24.
Radiation-induced bystander effects are a well-known phenomenon that are observed when treating cancer and other diseases after radiotherapy, and even after occupational exposure to radiation. However, little is known about the crosstalk between irradiated macrophages and endothelial cells that line the circulatory system, which may play a role in the development of atherosclerosis. In the current study, we found that the expression of inducible nitric oxide synthase (iNOS) and the intracellular level of nitric oxide (NO) in gamma-irradiated U937 macrophage cells were significantly increased. When human umbilical vein endothelial cells (HUVECs) were co-cultured with gamma-irradiated U937 cells, additional micronuclei (MN) and apoptosis were induced so that the plating efficiency of the bystander HUVECs decreased and P38 was overexpressed in the bystander HUVECs cells. In addition, the contents of vascular cell adhesion molecule 1 (VCAM-1) and the activities of matrix metalloproteinase-9 (MMP-9) in the culture medium of bystander HUVECs were increased. Furthermore, during cell co-culture the adhesive ability of irradiated U937 cells to the bystander HUVECs increased. When U937 cells were treated with 500 μM S-methylisothiourea sulfate (SMT) (iNOS inhibitor) before irradiation, and HUVECs were treated with 10 μM SB203580 (p38 inhibitor) before cell co-culture or treated with 20 μM c-PTIO (NO scavenger) in the co-culture medium, the bystander micronuclei and the amounts of VCAM-1 and MMP-9 in the medium of bystander HUVECs were diminished, and the ability of irradiated U937 cells adhering to HUVECs was also reduced, while the plating efficiency of bystander HUVECs partially recovered. These results demonstrated that irradiated U937 cells appear to release nitric oxide and thereby further trigger apoptosis and inflammatory responses in the bystander HUVECs through a p38-dependent pathway.
辐射诱导的旁观者效应是一种众所周知的现象，在癌症和其他疾病的放射治疗后，甚至在职业性辐射暴露后都会观察到这种现象。然而，人们对辐射照射的巨噬细胞和循环系统内皮细胞之间的串扰知之甚少，而这种串扰可能在动脉粥样硬化的发展中起作用。在本研究中，我们发现γ射线辐照 U937 巨噬细胞后，诱导型一氧化氮合酶（iNOS）的表达和细胞内一氧化氮（NO）水平显著增加。当人脐静脉内皮细胞（HUVEC）与γ射线辐照的 U937 细胞共培养时，会诱导额外的微核（MN）和细胞凋亡，使旁观者 HUVEC 的铺板效率降低，旁观者 HUVEC 细胞中 P38 过度表达。此外，在旁观者 HUVEC 细胞的培养基中，血管细胞黏附分子 1（VCAM-1）的含量和基质金属蛋白酶 9（MMP-9）的活性增加。此外，在细胞共培养过程中，辐照 U937 细胞对旁观者 HUVEC 的黏附能力增强。当 U937 细胞在辐照前用 500μM S-甲基异硫脲硫酸盐（SMT）（iNOS 抑制剂）处理，HUVEC 细胞在细胞共培养前用 10μM SB203580（p38 抑制剂）处理或在共培养培养基中用 20μM c-PTIO（NO 清除剂）处理时，旁观者微核以及旁观者 HUVEC 培养基中的 VCAM-1 和 MMP-9 含量减少，辐照 U937 细胞黏附 HUVEC 的能力也降低，而旁观者 HUVEC 的铺板效率部分恢复。这些结果表明，辐照 U937 细胞似乎释放一氧化氮，从而通过依赖 p38 的途径进一步触发旁观者 HUVEC 中的细胞凋亡和炎症反应。
