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病原体相关分子模式通过 TLR2 和 TLR4 途径引发炎症,并干扰卵巢优势卵泡中牛颗粒细胞的内分泌功能。

Pathogen-associated molecular patterns initiate inflammation and perturb the endocrine function of bovine granulosa cells from ovarian dominant follicles via TLR2 and TLR4 pathways.

机构信息

Institute of Life Science, School of Medicine, Swansea University, Singleton Park, Swansea, SA2 8PP, United Kingdom.

出版信息

Endocrinology. 2013 Sep;154(9):3377-86. doi: 10.1210/en.2013-1102. Epub 2013 Jul 3.

Abstract

Bacterial infections of the uterus or mammary gland commonly cause disease and infertility by perturbing growth and steroidogenesis of the dominant follicle in the ovary of cattle. Cells of the innate immune system use Toll-like receptors TLR2, TLR4, and TLR5 to recognize pathogen-associated molecular patterns (PAMPs) expressed by bacteria, leading to activation of MAPK and nuclear factor-κBκ pathways and production of inflammatory cytokines such as IL-1β and IL-6, and the chemokine IL-8. The present study tested whether granulosa cells from dominant follicles have functional TLR2, TLR4, and TLR5 pathways. Supernatants of primary bovine granulosa cells accumulated IL-1β, IL-6, and IL-8 when treated for 24 hours with Pam3CSK4 (PAM) that binds TLR2 or lipopolysaccharide (LPS) that binds TLR4 but not flagellin that binds TLR5. Granulosa cell responses to PAM or LPS were rapid, with increased phosphorylation of p38 and ERK1/2 within 30 minutes and increased abundance of IL6, IL1B, IL10, TNF, IL8, and CCL5 mRNA after 3 hours of treatment. Accumulation of IL-6 in response to PAM and LPS was attenuated using small interfering RNA targeting TLR2 and TLR4, respectively. Furthermore, treating granulosa cells with inhibitors targeting MAPK or nuclear factor-κB reduced the accumulation of IL-6 in response to LPS or PAM. Treatment with LPS or PAM reduced the accumulation of estradiol and progesterone, and the PAMPs reduced granulosa cell expression of CYP19A1 mRNA and protein. In conclusion, bacterial PAMPs initiate inflammation and perturb the endocrine function of bovine granulosa cells from dominant follicles via TLR2 and TLR4 pathways.

摘要

细菌感染子宫或乳腺通常会通过扰乱牛卵巢中优势卵泡的生长和类固醇生成来引起疾病和不孕。先天免疫系统的细胞使用 Toll 样受体 TLR2、TLR4 和 TLR5 来识别细菌表达的病原体相关分子模式 (PAMP),导致 MAPK 和核因子-κBκ 途径的激活以及炎性细胞因子(如 IL-1β 和 IL-6)和趋化因子 IL-8 的产生。本研究测试了优势卵泡中的颗粒细胞是否具有功能性 TLR2、TLR4 和 TLR5 途径。用 Pam3CSK4(TLR2 结合)或脂多糖(TLR4 结合)处理原代牛颗粒细胞 24 小时后,其上清液中积累了 IL-1β、IL-6 和 IL-8,但用鞭毛蛋白(TLR5 结合)处理则没有。颗粒细胞对 PAM 或 LPS 的反应迅速,p38 和 ERK1/2 的磷酸化在 30 分钟内增加,IL6、IL1B、IL10、TNF、IL8 和 CCL5mRNA 的丰度在 3 小时的处理后增加。用针对 TLR2 和 TLR4 的小干扰 RNA 分别靶向 PAM 和 LPS 可减弱 IL-6 的积累。此外,用针对 MAPK 或核因子-κB 的抑制剂处理颗粒细胞可减少 LPS 或 PAM 引起的 IL-6 积累。LPS 或 PAM 的处理减少了雌二醇和孕酮的积累,而 PAMPs 减少了颗粒细胞中 CYP19A1mRNA 和蛋白的表达。总之,细菌 PAMPs 通过 TLR2 和 TLR4 途径引发炎症并扰乱牛优势卵泡颗粒细胞的内分泌功能。

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