Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
J Clin Endocrinol Metab. 2021 Mar 25;106(4):1022-1040. doi: 10.1210/clinem/dgaa951.
Low-grade chronic inflammation is commonly seen in polycystic ovary syndrome (PCOS) patients with elevated levels of inflammatory cytokines in the endometrium.
This work aimed to increase the limited understanding of the mechanisms underlying cytokine synthesis and increased endometrial inflammation in PCOS patients.
Endometrial biopsy samples were collected from non-PCOS (n = 17) and PCOS (n = 22) patients either during the proliferative phase of the menstrual cycle or with hyperplasia. Endometrial explants were prepared from PCOS patients and underwent pharmacological manipulation in vitro. The expression and localization of toll-like receptor 2 (TLR2)/4, key elements of innate immune signal transduction and nuclear factor κB (NFκB) signaling pathways, and multiple cytokines were comprehensively evaluated by Western blotting, immunohistochemistry, and immunofluorescence in endometrial tissues.
We demonstrated the distribution of protein expression and localization associated with the significantly increased androgen receptor, TLR2, and TLR4-mediated activation of interferon regulatory factor-7 (IRF-7) and NFκB signaling, cytokine production, and endometrial inflammation in PCOS patients compared to non-PCOS patients with and without endometrial hyperplasia. In vitro experiments showed that 5-dihydrotestosterone (DHT) enhanced androgen receptor, TLR4, IRF-7, and p-NFκB p65 protein expression along with increased interferon α (IFNα) and IFNɣ abundance. The effects of DHT on IRF-7, p-NFκB p65, and IFN abundance were abolished by flutamide, an antiandrogen. Although 17β-estradiol (E2) decreased p-IRF-7 expression with little effect on TLR-mediated IRF7 and NFκB signaling or on cytokine protein levels, exposure to metformin alone or in combination with E2 suppressed interleukin-1 receptor-associated kinase 4 (IRAK4), p-IRF-7, IRF-7, IκB kinase α (IKKα), p-NFκB p65, IFNɣ, and tumor necrosis factor α protein expression.
Cytokine synthesis and increased endometrial inflammation in PCOS patients are coupled to androgen-induced TLR4/IRF-7/NFκB signaling, which is inhibited by metformin treatment.
低度慢性炎症常见于子宫内膜中炎症细胞因子水平升高的多囊卵巢综合征（PCOS）患者。
本研究旨在深入了解 PCOS 患者中细胞因子合成和子宫内膜炎症增加的潜在机制。
在增生期或增生期采集非 PCOS（n=17）和 PCOS（n=22）患者的子宫内膜活检样本。从 PCOS 患者中制备子宫内膜外植体，并在体外进行药理学处理。通过 Western blot、免疫组化和免疫荧光，全面评估子宫内膜组织中 Toll 样受体 2（TLR2）/4、先天免疫信号转导和核因子 kappa B（NFκB）信号通路的关键元件以及多种细胞因子的表达和定位。
与非 PCOS 患者相比，我们在 PCOS 患者中证实了与明显增加的雄激素受体、TLR2 和 TLR4 介导的干扰素调节因子-7（IRF-7）和 NFκB 信号转导、细胞因子产生和子宫内膜炎症相关的蛋白表达和定位分布。与非 PCOS 患者的增生期或增生期相比，子宫内膜增生期。体外实验表明，5-二氢睾酮（DHT）增强了雄激素受体、TLR4、IRF-7 和 p-NFκB p65 蛋白表达，同时增加了干扰素 α（IFNα）和 IFNɣ 的丰度。DHT 对 IRF-7、p-NFκB p65 和 IFN 丰度的影响被抗雄激素氟他胺所消除。尽管 17β-雌二醇（E2）降低了 p-IRF-7 的表达，但对 TLR 介导的 IRF7 和 NFκB 信号转导或细胞因子蛋白水平几乎没有影响，单独使用二甲双胍或与 E2 联合使用可抑制白细胞介素-1 受体相关激酶 4（IRAK4）、p-IRF-7、IRF-7、IκB 激酶α（IKKα）、p-NFκB p65、IFNɣ 和肿瘤坏死因子 α 蛋白表达。
PCOS 患者的细胞因子合成和子宫内膜炎症增加与雄激素诱导的 TLR4/IRF-7/NFκB 信号转导有关，二甲双胍治疗可抑制该信号转导。
