Advanced glycation end products (AGEs) affect the follicular microenvironment. The close relationship between AGEs, proinflammatory cytokine production and activation of the unfolded protein response (UPR), which involves activating transcription factor 4 (ATF4), is crucial for regulation of various cellular functions. We examined whether accumulation of AGEs in follicles was associated with proinflammatory cytokine production and activation of the UPR in granulosa cells and decreased oocyte developmental competence. Concentrations of AGEs, soluble receptor for AGE (sRAGE), interleukin (IL)-6 and IL-8 in follicular fluid (FF) were examined by ELISAs in 50 follicles. mRNA expression of ATF4, IL-6 and IL-8 in cumulus cells (CCs) were examined by quantitative RT-PCR in 77 samples. Cultured human granulosa-lutein cells (GLCs) were treated with AGE-bovine serum albumin (BSA) alone or following transfection of ATF4-targeting small interfering RNA. The AGE concentration and the AGE/sRAGE ratio in FF were significantly higher in follicles containing oocytes that developed into poor-morphology embryos (group I) than those with good-morphology embryos (group II). When compared with sibling follicles from the same patients, the AGE/sRAGE and concentrations of IL-6 and IL-8 in FF, as well as ATF4, IL-6 and IL-8 mRNA expression in CCs, were significantly higher in group I follicles than group II. AGE treatment increased mRNA expression of ATF4, IL-6 and IL-8 in cultured GLCs. Knockdown of ATF4 abrogated the stimulatory effects of AGE on mRNA expression and protein secretion of IL-6 and IL-8. Our findings support the idea that accumulation of AGEs in follicles reduces oocyte competence by triggering inflammation via activation of ATF4 in the follicular microenvironment.

中文翻译：

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卵泡中晚期糖基化终产物的积累与卵母细胞发育能力差有关。

晚期糖基化终产物（AGEs）影响滤泡微环境。AGEs，促炎细胞因子的产生和未折叠蛋白应答（UPR）的激活之间的密切关系，涉及激活转录因子4（ATF4），对于调节各种细胞功能至关重要。我们检查了卵泡中AGEs的积累是否与促炎细胞因子的产生和颗粒细胞中UPR的激活以及卵母细胞发育能力的降低有关。通过ELISA检测50个卵泡中的AGEs，AGE的可溶性受体（sRAGE），白介素（IL）-6和IL-8的浓度。通过定量RT-PCR检测了77个样本中卵丘细胞（CCs）中ATF4，IL-6和IL-8的mRNA表达。单独或在转染靶向ATF4的小干扰RNA后，用AGE-牛血清白蛋白（BSA）处理培养的人类颗粒-叶黄素细胞（GLC）。FF卵中的AGE浓度和AGE / sRAGE比在含有发育为形态不良的胚胎的卵母细胞的卵泡（组I）中明显高于形态良好的胚胎的卵泡（II组）。与同一患者的同胞卵泡相比，I组的FF中AGE / sRAGE和IL-6和IL-8的浓度以及CCs中ATF4，IL-6和IL-8 mRNA的表达均显着较高。卵泡比第二组。AGE处理可提高培养的GLC中ATF4，IL-6和IL-8的mRNA表达。减少ATF4消除了AGE对IL-6和IL-8的mRNA表达和蛋白质分泌的刺激作用。