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Abstract：
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.
摘要：
白细胞介素18(IL-18)是一种多效促炎细胞因子,与卵泡发育停滞和无排卵相关,是PCOS的典型病理变化。卵泡膜细胞（TC）在卵泡生长和闭锁中起关键作用。但IL-18能否直接影响卵巢TC的功能尚不清楚。因此,本研究的目的是确定IL-18对牛TCs增殖和类固醇生成的影响，并探讨IL-18对卵泡生成的生物学作用。这项工作表明，在300-1000pg/mL时，IL-18导致细胞增殖的时间和剂量依赖性增加（P<0.05）。IL-18增加17-羟孕酮（17OHP4）和雄烯二酮（A2）的分泌，并上调关键类固醇生成相关基因CYP11A1和CYP17A1（P<0.05）。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(3~6mm)TC中表达,而在大卵泡(8~22mm)TC中表达.我们还发现,IL-18对TC的刺激作用可以早在培养4小时时加入IL-18BP而逆转,并在16小时达到峰值。我们得出结论，IL-18似乎靶向牛的TC，并提示这种细胞因子在卵巢功能中的重要作用。目前的发现进一步证实了IL-18在与卵泡发育不良和卵巢TC过度生长相关的病症(如PCOS)中的潜在作用。但需要更多的研究来进一步了解IL-18在卵泡膜细胞中的作用机制及其在卵泡发育中的确切作用。
