Interleukin 18 (IL‐18) is a pleiotropic pro‐inflammatory cytokine and is associated with arrested follicle development and anovulation which are the typical pathological changes of PCOS. Theca cells (TCs) have a key role in follicular growth and atresia. But whether IL‐18 can directly affect ovarian TCs function is unknown. Therefore, the objective of this study was to determine the effect of IL‐18 on proliferation and steroidogenesis of bovine TCs and to explore the biological effect of IL‐18 on folliculogenesis. This work revealed that at 300‐1000 pg/mL, IL‐18 led to a time‐ and dose‐dependently increase in cell proliferation (P < .05). IL‐18 increased 17‐hydroxyprogesterone (17OHP4) and androstenedione (A2) secretion with up‐regulation of key steroidogenesis‐related genes CYP11A1 and CYP17A1 (P < .05). Furthermore, our data demonstrated that the IL‐18R protein is predominantly expressed in small‐follicle (3‐6 mm) TCs than large follicles (8‐22 mm) by immunohistochemistry. We also found that the stimulation effects of IL‐18 on TCs can be reversed with the addition of IL‐18BP as early as at 4 hours of culture and reached the peak at 16 hours. We conclude that IL‐18 appears to target TCs in bovine, and suggest an important role for this cytokine in ovarian function. Present findings further validate potential effects of IL‐18 in the conditions associated with follicular dysplasia and excessive growth of ovarian TCs (such as PCOS). But additional research is needed to further understand the mechanism of action of IL‐18 in theca cells as well as its precise role in folliculogenesis.

中文翻译：

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IL-18 对牛膜细胞增殖和类固醇生成的影响：在多囊卵巢综合征发病机制中的可能作用

白细胞介素 18 (IL-18) 是一种多效性促炎细胞因子，与多囊卵巢综合征的典型病理变化——卵泡发育停滞和无排卵有关。膜细胞 (TC) 在卵泡生长和闭锁中起关键作用。但IL-18是否能直接影响卵巢TCs功能尚不清楚。因此，本研究的目的是确定 IL-18 对牛 TC 增殖和类固醇生成的影响，并探索 IL-18 对卵泡发生的生物学作用。这项工作表明，在 300-1000 pg/mL 时，IL-18 导致细胞增殖呈时间和剂量依赖性增加 ( P  < .05)。IL-18 增加 17-羟基孕酮 (17OHP4) 和雄烯二酮 (A2) 的分泌，同时上调关键的类固醇生成相关基因 CYP11A1 和 CYP17A1 ( P < .05)。此外，我们的数据表明，通过免疫组织化学，IL-18R 蛋白主要在小卵泡 (3-6 mm) TC 中表达，而不是大卵泡 (8-22 mm)。我们还发现 IL-18 对 TCs 的刺激作用最早可以在培养 4 小时时通过添加 IL-18BP 来逆转，并在 16 小时达到峰值。我们得出结论，IL-18 似乎靶向牛中的 TC，并表明这种细胞因子在卵巢功能中的重要作用。目前的研究结果进一步验证了 IL-18 在与卵泡发育不良和卵巢 TC（如 PCOS）过度生长相关的疾病中的潜在影响。但是需要更多的研究来进一步了解 IL-18 在膜细胞中的作用机制以及它在卵泡发生中的确切作用。