Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland.
Immunol Lett. 2012 Sep;147(1-2):29-33. doi: 10.1016/j.imlet.2012.05.005. Epub 2012 Jun 12.
Oxidative stress and inflammation are known to be associated with age-related macular degeneration (AMD). Retinal pigment epithelial (RPE) cells play the principal role in the immune defense of macula, and their dysfunction is a crucial event leading to clinically relevant changes seen in AMD. In the present study, we have examined the ability of oxidative stress to activate inflammasome signaling in the human ARPE-19 cells by adding the lipid peroxidation end product 4-hydroxynonenal (HNE) to cell cultures pre-treated or not treated with the endotoxin, LPS. Our results indicate that LPS and HNE significantly increased the production of IL-6 and IL-18, respectively. LPS treatment preceding HNE induced an even greater increase in the production of IL-18 than HNE alone. In addition to IL-18, HNE significantly increased the production of IL-1β. The productions of IL-1β and IL-18 were reduced in the cell cultures pre-treated with the Caspase-1 inhibitor. PCR analysis revealed that HNE induced an over 5-fold increase in the amount of NLRP3 mRNA compared to control cells; LPS had no effect. In conclusion, our present data suggest that oxidative stress can activate NLRP3 inflammasomes in RPE cells which occupy center stage in the pathogenesis of AMD.
氧化应激和炎症与年龄相关性黄斑变性（AMD）有关。视网膜色素上皮（RPE）细胞在黄斑的免疫防御中起主要作用，其功能障碍是导致 AMD 中出现临床相关变化的关键事件。在本研究中，我们通过向预处理或未预处理内毒素 LPS 的人 ARPE-19 细胞培养物中添加脂质过氧化终产物 4-羟基壬烯醛（HNE），研究了氧化应激激活炎症小体信号的能力。结果表明，LPS 和 HNE 分别显著增加了 IL-6 和 IL-18 的产生。LPS 处理先于 HNE 诱导 IL-18 的产生增加幅度甚至大于 HNE 单独处理。除了 IL-18 之外，HNE 还显著增加了 IL-1β的产生。用 Caspase-1 抑制剂预处理细胞培养物后，IL-1β和 IL-18 的产生减少。PCR 分析显示，与对照细胞相比，HNE 诱导 NLRP3 mRNA 的量增加了 5 倍以上；LPS 没有影响。总之，我们目前的数据表明，氧化应激可以激活 RPE 细胞中的 NLRP3 炎症小体，RPE 细胞在 AMD 的发病机制中占据中心地位。
