ENDOCRINE-IMMUNE INTERACTIONS

存在临床上有用的雌激素、雄激素和 矿物皮质激素。糖皮质激素或孕激素的拮抗剂 具有潜在临床应用价值的药物是最近发现的。这个 本项目的目的是开发和研究分子机制。 对这两种情况的作用和拮抗剂的人类应用 类固醇的种类。我们已经测试了一种糖皮质激素-孕激素的原型 Roussel-UCLAF新近开发的拮抗剂(RU 486)。这种化合物 对人类糖皮质激素和孕激素受体有很强的亲和力 在小型实验动物身上没有激动剂效应。习惯于 非人灵长类或人类RU 486导致血浆持续升高 促肾上腺皮质激素、皮质醇和精氨酸加压素，所有这些变化都可以通过 以前使用过糖皮质激素(地塞米松)。这 提示抗糖皮质激素可用于挑战 下丘脑-垂体-肾上腺轴，当需要临床测试时 患有这一轴紊乱的患者。类风湿性关节炎的抗糖皮质激素治疗 促肾上腺皮质激素异位分泌所致严重库欣综合征 肾上腺皮质肿瘤引起的临床症状缓解 皮质醇过多症。RU 486增强炎症/免疫反应 对完好动物的标准刺激，表明糖皮质激素 在生理水平上发挥抗炎/免疫抑制作用。 我们最近证实促肾上腺皮质激素释放激素(CRH)是 在发炎部位局部产生，具有深刻的促炎作用 自分泌/旁分泌水平的炎症效应。我们把这个叫做 “免疫”CRH。糖皮质激素抑制，RU 486显著增强 炎症部位局部分泌免疫CRH。免疫CRH 发现于卵巢和子宫内膜，在那里它可能参与 排卵、黄体溶解和月经的炎症现象。RU 486 允许对大鼠的中枢神经系统缺陷进行鉴定 容易患关节炎。在这些动物中，糖皮质激素对 应激介质不足以抑制免疫系统 侮辱。实际的缺陷是全局的，并且位于 下丘脑CRH神经元，对所有已知的信息反应很差 兴奋剂，包括几种细胞因子，以及5-羟色胺， 乙酰胆碱和去甲肾上腺素。这种病理生理机制是 新的及其与人类关节炎和自身免疫性疾病的相关性将是 检查过了。

Clinically useful antagonists exist for estrogens, androgens, and mineralocorticoids. Antagonists for the glucocorticoids or the progestins with potential clinical usefulness have been discovered recently. The objective of this project is to develop and study the molecular mechanisms of action and the human applications of the antagonists for both of these classes of steroids. We have tested a prototype glucocorticoid-progestin antagonist (RU 486) developed recently by Roussel-UCLAF. This compound has strong affinities for the human glucocorticoid and progestin receptor and is devoid of agonist effects in small experimental animals. Given to nonhuman primates or man RU 486 causes prolonged elevations of plasma ACTH, cortisol and arginine vasopressin, all changes preventable by previous administration of a glucocorticoid (dexamethasone). This suggests that antiglucocorticoids could be used for challenging the hypothalamic-pituitary-adrenal axis, when clinical testing is required in patients with disorders of this axis. Antiglucocorticoid therapy of patients with severe Cushing's syndrome due to ectopic ACTH secretion or adrenocortical tumors causes remission of the clinical manifestations of hypercortisolism. RU 486 potentiated the inflammatory/immune response to a standard stimulus in intact animals, suggesting that glucocorticoids exert anti-inflammatory/immunosuppressive effects at physiological levels. We recently demonstrated that corticotropin releasing hormone (CRH) is produced locally at the site of inflammation and has profound pro- inflammatory effects at an autocrine/paracrine level. We have called this "immune" CRH. Glucocorticoids suppress, and RU 486 markedly augments local secretion of immune CRH at an inflammatory site. Immune CRH was found in the ovary and endometrium where it may participate in the inflammatory phenomena of ovulation, luteolysis, and menstruation. RU 486 allowed the identification of a central nervous system defect in rats prone to arthritis. In these animals the glucocorticoid response to stress-mediators is inadequate to restrain the immune system following an insult. The actual defect is global and located at the level of the hypothalamic CRH neuron, which responds poorly to all its known stimulants, including several cytokines, as well as serotonin, acetylcholine and norepinephrine. This pathophysiologic mechanism is novel and its relevance to human arthritis and autoimmune disease will be examined.