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的内分泌和免疫系统之间相互作用的了解。应激激素糖皮质激素和儿茶酚胺抑制单核巨噬细胞分泌白介素12，刺激白介素10的分泌，导致从Thper1向Ther2定向免疫的转变。另一方面，一些免疫系统的产物，如细胞因子肿瘤坏死因子-α、IL-1和IL-6，激活了下丘脑-垂体-肾上腺轴，并通过它抑制和抑制炎症免疫反应。微灌注法原位检测的人类脂肪不仅产生瘦素，还产生肿瘤坏死因子-α和白介素6。这些细胞因子的分泌有一个受睡眠影响的昼夜节律，而它们的循环水平随着BMI的增加而成比例地增加，并因内脏肥胖而进一步升高。抑郁症、特发性失眠和睡眠呼吸暂停患者的IL-6浓度升高。Enbrel是一种抗肿瘤坏死因子-α的生物制剂，可降低IL-6浓度，改善睡眠呼吸暂停指数，并减少嗜睡。在抑郁症患者中，IL-6的昼夜节律与早晨的最高水平相反，这与这些患者的影响密切相关。睡眠不足会导致表现下降，疲劳感增加，伴随着血浆IL-6浓度的升高。午睡会降低IL-6，提高运动能力。我们最近发现了两个小分子，一个是IL-6拮抗剂，一个是PPAR-Delta激动剂，它们通过抑制STAT3而具有抗炎活性。前者的化合物TB-2-081与IL-6型受体的gp130亚单位相互作用，不仅能阻断IL-6的活性，还能阻断LIF、肿瘤素M和IL-11的活性。细胞的一个主要变化是抑制了STAT3转录因子的酪氨酸磷酸化。后者GW50516可抑制肝细胞产生几种急性期反应物，从而显示出主要的抗炎活性。这种作用也是通过抑制反应基因启动子上的STAT3活性来实现的。我们早些时候已经证明，促肾上腺皮质激素释放激素(CRH)是在炎症部位局部产生的，并在自分泌旁分泌水平上具有深刻的促炎作用。CRH是肥大细胞的一种强有力的脱颗粒物质，这种现象可以被一种非肽CRH拮抗剂抑制，这种拮抗剂专用于1型受体，称为antalarmin。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的癫痫发作和内脏疼痛。CRH存在于卵巢和子宫内膜，参与排卵、黄体溶解、胚泡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 monocytesmacrophages, 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 inflammatoryimmune 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. Napping decreases IL-6 and improves performance. We recently showed that two small molecules an IL-6 antagonist and a PPAR-delta agonist have anti-inflammatory activity via STAT3 inhibition. The former compound, TB-2-081, interacted with the gp130 subunit of the IL-6 -type receptors and blocked the activity not only of IL-6 but also of LIF, Oncostatin M and IL-11. A major change in the cell was the inhibition of the tyrosine phosphorylation of the STAT3 transcription factor. The latter compound, GW50516, inhibited the production of several acute phase reactants by hepatic cells showing thus major anti-inflammatory activity. This effect was also mediated by inhibition of STAT3 activity at the promoter of responsive genes. We had demonstrated earlier that corticotropin-releasing hormone (CRH) is produced locally at sites of inflammation and has profound pro-inflammatory effects at an autocrineparacrine 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.