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，刺激单核/巨噬细胞分泌白介素10，导致从Ther1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具有昼夜节律，受睡眠的影响，而它们的循环水平与BMI成比例增加，并因内脏肥胖而进一步升高。我们最近证明促肾上腺皮质激素释放激素(CRH)是在局部炎症部位产生的，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。这种拮抗剂具有显著的全身抗炎作用。CRH存在于卵巢和子宫内膜，可能参与排卵、黄体溶解、胚泡着床、月经等炎症现象。Antalarmin阻断大鼠着床和绵羊分娩，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-a (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. 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. CRH was found in the ovary and endometrium where it may participate in the inflammatory phenomena of ovulation, luteolysis, blastocyst implantation, and menstruation. Antalarmin blocked implantation in rats and labor in sheep, suggesting that CRH antagonists may have clinical applications in reproductive medicine.