Endocrine-immune-reproductive System Interactions

这个项目的目的是增加我们对实验动物和人类内分泌和免疫系统之间相互作用的理解。应激激素糖皮质激素和儿茶酚胺抑制白细胞介素(IL)-12的分泌，并刺激单核/巨噬细胞分泌IL-10，导致从Thelper1定向免疫转向thelper2定向免疫。另一方面，一些免疫系统产物，如细胞因子肿瘤坏死因子- α (tnf - α)， IL-1和IL-6激活下丘脑-垂体-肾上腺轴，并通过它抑制和抑制炎症/免疫反应。微灌注原位检测的人脂肪不仅产生瘦素，还产生tnf - α和IL-6。这些细胞因子的分泌具有受睡眠影响的昼夜节律，而它们的循环水平与BMI成比例地增加，并因内脏肥胖而进一步升高。IL-6浓度在抑郁症、特发性失眠和睡眠呼吸暂停患者中升高。Enbrel是一种抗tnf - α的生物制剂，可降低IL-6浓度，改善睡眠呼吸暂停指数，减少嗜睡。在抑郁症患者中，IL-6的昼夜节律是颠倒的，早晨的IL-6水平最高，这与这些患者的影响密切相关。睡眠不足会导致表现下降，并增加与血浆IL-6浓度升高相关的疲劳。我们最近证明促肾上腺皮质激素释放激素（CRH）在炎症部位局部产生，并在自分泌/旁分泌水平具有深刻的促炎作用。CRH是一种有效的肥大细胞脱颗粒剂，这种现象可以被一种非肽CRH拮抗剂抑制，这种拮抗剂专门针对1型受体，称为抗塔拉霉素。该拮抗剂在类风湿性关节炎动物模型中具有显著的全身抗炎作用，并在动物模型中阻断志贺氏菌相关癫痫发作和内脏疼痛。CRH见于卵巢和子宫内膜，参与排卵、卵泡溶解、囊胚着床和月经等炎症现象。Antalarmin阻断大鼠胚胎着床和绵羊分娩，提示CRH拮抗剂可能在生殖医学中有临床应用。

The purpose of this project is to increase our understanding of the interactions between the endocrine and immune systems in both experimental animals and humans. The stress hormones glucocorticoids and catecholamines inhibit the secretion of Interleukin(IL)-12 and stimulate the secretion of IL-10 by monocytes/macrophages, leading to a shift from Thelper1 to Thelper2-directed immunity. On the other hand, several immune system products, such as the cytokines Tumor Necrosis Factor-alpha (TNF-alpha), IL-1, and IL-6 activate the hypothalamic-pituitary-adrenal axis and through it suppress and restrain the inflammatory/immune response. Human fat examined in situ by microperfusion produces not only leptin, but also TNF-alpha and IL-6. The secretion of these cytokines has a circadian rhythm that is influenced by sleep, while their circulating levels increase proportionally to the BMI and are furher elevated by visceral adiposity. IL-6 concentrations are elevated in patients with depression, idiopathic insomnia and sleep apnea. Enbrel, an anti-TNF-alpha biological, decreases IL-6 concentrations, improves sleep apnea indices and decreases sleepiness. In depression, the circadian rhythm of IL-6 is inverted with highest levels in the morning, correlating strongly with the affect of these patients. Sleep deprivation results in a fall in performance and an increase in fatigue associated with an elevation of plasma IL-6 concentrations. We recently demonstrated that corticotropin-releasing hormone (CRH) is produced locally at sites of inflammation and has profound pro-inflammatory effects at an autocrine/paracrine level. CRH is a potent degranulator of mast cells, a phenomenon that can be inhibited by a nonpeptide CRH antagonist, specific for type 1 receptors called antalarmin. This antagonist has marked systemic anti-inflammatory actions in an animal model of rheumatoid arthritis, and blocks Shigella -related seizures and visceral pain in animal models. CRH was found in the ovary and endometrium where it participates in the inflammatory phenomena of ovulation, luteolysis, blastocyst implantation, and menstruation. Antalarmin blocked embryo implantation in rats and labor in sheep, suggesting that CRH antagonists may have clinical applications in reproductive medicine.