IL-6在产后疲乏影响泌乳信号通路中的作用机制研究

Detrimental effect of postpartum fatigue on lactation are highly concerned. Prolactin (PRL) binding with Prolactin Receptor (PRLR) in mammary epithelial cell activates Jak2/Stat5 signaling pathway, which starts the synthesis of milk protein. PRL also participates in stress response. The level of serum PRL rises in the ones with chronic fatigue, but a decrease of lactation has been identified in postpartum women with fatigue. Cytokine IL-6 is a molecular marker of fatigue symptoms. It is reported that IL-6 takes part in the regulation of Stat5. We hypothesized that in the condition of postpartum fatigue, human body may down regulate the expression of PRLR in mammary gland, affect the binding of PRL to PRLR, or competitively inhibit the Stat5 signaling pathway. In this study, a rat model of postpartum fatigue will be established, and correlation between IL-6 and PRLR, receptor binding rate，and Stat5 will be analyzed. Then, cytokine IL-6 injection will be applied to healthy lactation rats to detect their activity of lactational signaling pathway. At last, primary culture of mammary epithelial cells of rats within lactation period is conducted using IL-6 culture medium to explore the role of IL-6 in lactation. Finally, the role of IL-6 in the mechanism of effect of postpartum fatigue on lactational signaling pathway is explored in vivo and in vitro.

产后疲乏影响泌乳已受到广泛关注。乳汁合成通过PRL与PRLR结合，激活Jak2/Stat5信号通路启动。PRL参与泌乳及应激反应。慢性疲乏女性PRL水平高于正常，但长期疲乏状态却抑制产妇乳汁分泌，具体作用机制不清。细胞因子IL-6是疲乏的分子标志物。研究发现IL-6可调节Stat5表达活性。我们推测，产后疲乏时机体通过IL-6下调乳腺PRLR表达；或阻碍PRL与PRLR结合；或竞争性抑制Stat5泌乳信号通路，阻碍乳汁合成。本研究拟建立产后疲乏大鼠模型，分析IL-6与乳腺PRLR、受体结合率及Stat5表达相关性；接着IL-6静脉注射健康泌乳大鼠，检测泌乳信号通路表达活性；然后体外培养泌乳大鼠乳腺上皮细胞，IL-6预处理培养基，观察IL-6对乳腺上皮细胞泌乳基因表达的影响。最终明确IL-6在产后疲乏影响泌乳中的作用机制。

产后疲乏是世界范围内的常见疾病。本研究主要探讨产后疲乏抑制乳腺泌乳的机制。首先通过强迫产后大鼠水中站立，构建大鼠疲乏模型，并从脑力疲乏及体力疲乏评价模型有效性。接着通过检测疲乏大鼠IL-6、PRL PRLR、JAK2、STAT-5的表达，光镜和电镜观察大鼠乳腺的显微结构，探讨疲乏对泌乳信号通路的影响。并通过泌乳期大鼠乳腺组织原代培养细胞，采用IL-6及其拮抗剂预处理培养基，检测泌乳信号通路表达活性。从体内及体外实验探讨IL-6在产后疲乏调控泌乳信号通路中的作用机制。结果发现产后疲乏大鼠由于泌乳不足导致幼仔生长迟缓。产后疲乏大鼠乳腺IL-6表达下降，垂体PRL及其下游信号通路JAK2/STAT5的表达下调。PRLR通过反馈性抑制，表达上调。产后疲乏导致分泌乳腺的功能退化，乳腺小叶缩小，乳腺泡数量减少。透射电镜下见乳腺上皮细胞质内乳蛋白颗粒和脂肪滴分泌减少。当IL-6拮抗剂预处理培养基后，乳腺上皮细胞JAK2/STAT5表达下调；而IL-6浓度增加后，JAK2/STAT5表达增加。可见产后疲乏大鼠乳腺IL-6水平下调，导致PRL/PRLR介导的JAK2/STAT5泌乳信号通路表达下降，从而导致泌乳减少。产后疲乏可通过IL-6水平调节PRL及PRL介导的泌乳信号通路调节泌乳。.本研究成功构建产后疲乏大鼠模型，并阐明了产后疲乏阻碍泌乳发生的机制。研究共发表论文9篇，其中SCI收录2篇，中华系列杂志1篇，北图核心期刊论文3篇，SCD收录2篇。申报发明专利4项，授权发明专利1项，转让发明专利1项。研究成果获得上海护理科技二等奖，获得市级人才项目1项，国内特邀讲座1次，培养学生申报省级大学生/研究生创新计划项目3项，本科生一作发表北图核心期刊论文2篇，申报发明专利1项。