Endocrine-immune-reproductive System Interactions

该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的分泌并刺激单核细胞/巨噬细胞分泌IL-10，导致从Thelper 1向Thelper 2定向免疫的转变。另一方面，几种免疫系统产物，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/免疫应答。通过微灌注原位检测的人类脂肪不仅产生瘦素，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，并且通过内脏肥胖进一步升高。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TNF-α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。在抑郁症中，IL-6的昼夜节律是颠倒的，早上的水平最高，与这些患者的影响密切相关。我们最近证实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是一种有效的肥大细胞去增殖剂，这种现象可以被一种非肽CRH拮抗剂抑制，这种拮抗剂对1型受体有特异性，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。CRH存在于卵巢和子宫内膜中，参与排卵、黄体溶解、胚泡着床和月经的炎症现象。Antalarmin阻断大鼠胚胎着床和绵羊分娩，表明CRH拮抗剂可能在生殖医学中具有临床应用。

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. 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. 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.