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首页> 外文期刊>Cytokine >Parainflammation associated with advanced glycation endproduct stimulation of RPE in vitro: Implications for age-related degenerative diseases of the eye
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Parainflammation associated with advanced glycation endproduct stimulation of RPE in vitro: Implications for age-related degenerative diseases of the eye

机译：副炎症与体外RPE的糖基化终末产物的刺激相关：对年龄相关性眼部退行性疾病的影响

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Age related macular degeneration (AMD) is one of the leading causes of blindness in Western society. A hallmark of early stage AMD are drusen, extracellular deposits that accumulate in the outer retina. Advanced glycation endproducts (AGE) accumulate with aging and are linked to several age-related diseases such as Alzheimer's disease, osteoarthritis, atherosclerosis and AMD. AGE deposits are found in drusen and in Bruch's membrane of the eye and several studies have suggested its role in promoting oxidative stress, apoptosis and lipofuscin accumulation. Recently, complement activation and chronic inflammation have been implicated in the pathogenesis of AMD. While AGEs have been shown to promote inflammation in other diseases, whether it plays a similar role in AMD is not known. This study investigates the effects of AGE stimulation on pro- and anti-inflammatory pathways in primary culture of human retinal pigment epithelial cells (RPE). Differential gene expression studies revealed a total of 41 up- and 18 down-regulated RPE genes in response to AGE stimulation. These genes fell into three categories as assessed by gene set enrichment analysis (GSEA). The main categories were inflammation (interferon-induced, immune response) and proteasome degradation, followed by caspase signaling. Using suspension array technology, protein levels of secreted cytokines and growth factors were also examined. Anti-inflammatory cytokines including IL10, IL1ra and IL9 were all overexpressed. Pro-inflammatory cytokines including IL4, IL15 and IFN-γ were overexpressed, while other pro-inflammatory cytokines including IL8, MCP1, IP10 were underexpressed after AGE stimulation, suggesting a para-inflammation state of the RPE under these conditions. Levels of mRNA of chemokine, CXCL11, and viperin, RSAD2, were up-regulated and may play a role in driving the inflammatory response via the NF-kB and JAK-STAT pathways. CXCL11 was strongly immunoreactive and associated with drusen in the AMD eye. The pathways and novel genes identified here highlight inflammation as a key response to AGE stimulation in primary culture of human RPE, and identify chemokine CXCL11 as putative novel agent associated with the pathogenesis of AMD.
机译：与年龄有关的黄斑变性（AMD）是西方社会失明的主要原因之一。早期AMD的标志是玻璃膜疣，在视网膜外部积聚的细胞外沉积物。晚期糖化终产物（AGE）随着年龄的增长而积累，并与多种与年龄有关的疾病有关，例如阿尔茨海默氏病，骨关节炎，动脉粥样硬化和AMD。在玻璃膜疣和眼睛的布鲁赫膜中发现了AGE沉积物，一些研究表明其在促进氧化应激，细胞凋亡和脂褐素积累中的作用。最近，补体激活和慢性炎症与AMD的发病机理有关。尽管已证明AGEs可以促进其他疾病的炎症，但尚不清楚它是否在AMD中起类似作用。这项研究调查了AGE刺激对人视网膜色素上皮细胞（RPE）原代培养中促炎和抗炎途径的影响。差异基因表达研究表明，响应AGE刺激，共有41个上调的RPE基因和18个下调的RPE基因。通过基因集富集分析（GSEA）评估，这些基因分为三类。主要类别是炎症（干扰素诱导的免疫应答）和蛋白酶体降解，其次是胱天蛋白酶信号转导。使用悬浮阵列技术，还检查了分泌的细胞因子和生长因子的蛋白质水平。包括IL10，IL1ra和IL9在内的抗炎细胞因子均过表达。 AGE刺激后，包括IL4，IL15和IFN-γ在内的促炎细胞因子过表达，而在AGE刺激后，包括IL8，MCP1，IP10在内的其他促炎细胞因子则过表达，表明在这些条件下RPE处于准炎症状态。趋化因子，CXCL11和viperin，RSAD2的mRNA水平上调，并可能在通过NF-kB和JAK-STAT途径驱动炎症反应中起作用。 CXCL11具有强烈的免疫反应性，并与AMD眼的玻璃疣相关。此处鉴定的途径和新基因突出了炎症，将其作为人类RPE原代培养中AGE刺激的关键反应，并将趋化因子CXCL11鉴定为与AMD发病机理相关的推定新药。

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