Toll 样受体 4 抑制人颗粒细胞中雌二醇的分泌 NF-κB 信号通路。

Toll-Like Receptor 4 Inhibits Estradiol Secretion NF-κB Signaling in Human Granulosa Cells.

机构信息

Department of Reproductive Endocrinology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China.

Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.

出版信息

Front Endocrinol (Lausanne). 2021 Mar 12;12:629554. doi: 10.3389/fendo.2021.629554. eCollection 2021.

Toll-like receptor 4 (TLR4) may play a critical role in regulating follicular development. Data are scarce on the role of TLR4 in the follicle. This study investigated the effects of TLR4 on steroidogenesis in human granulosa cells. Immunohistochemical analysis revealed stage-specific expression of TLR4 in the mouse ovarian cycle, and immunofluorescence showed TLR4 expression in the human granulosa-like tumor cell line (KGN). TLR4 agonist lipopolysaccharides (LPS) significantly inhibited follicular development and synthesis of estradiol (E2) in mice. In KGN cells, TLR4 activation significantly inhibited CYP19A1, FSHR and StAR, and TLR4 inhibition reversed these effects. TLR4 activation also inhibited forskolin-induced secretion of E2 by inhibiting CYP19A1, with no effect on progesterone. Further studies showed activation of p38, JNK and NF-κB signaling after TLR4 activation. Subsequent analyses showed that an NF-κB antagonist reversed the inhibitory effects on CYP19A1 expression and E2 secretion. Together, our results suggest that TLR4 activation may suppress CYP19A1 expression and E2 secretion NF-κB signaling in human granulosa cells, with important implications for the regulation of ovarian pathophysiology.

Toll 样受体 4（TLR4）可能在调节卵泡发育中发挥关键作用。关于 TLR4 在卵泡中的作用的数据很少。本研究探讨了 TLR4 对人颗粒细胞甾体生成的影响。免疫组织化学分析显示 TLR4 在小鼠卵巢周期中具有阶段特异性表达，免疫荧光显示 TLR4 在人颗粒样肿瘤细胞系（KGN）中表达。TLR4 激动剂脂多糖（LPS）显著抑制小鼠卵泡发育和雌二醇（E2）的合成。在 KGN 细胞中，TLR4 激活显著抑制 CYP19A1、FSHR 和 StAR，而 TLR4 抑制逆转了这些作用。TLR4 激活还通过抑制 CYP19A1 抑制了 forskolin诱导的 E2 分泌，而对孕酮没有影响。进一步的研究表明，TLR4 激活后会激活 p38、JNK 和 NF-κB 信号通路。随后的分析表明，NF-κB 拮抗剂逆转了对 CYP19A1 表达和 E2 分泌的抑制作用。综上所述，我们的结果表明，TLR4 激活可能通过 NF-κB 信号通路抑制人颗粒细胞中 CYP19A1 的表达和 E2 的分泌，这对卵巢病理生理学的调节具有重要意义。