ENDOCRINE-IMMUNE INTERACTIONS

内分泌免疫相互作用

• 批准号: 2575628
• 负责人: G P CHROUSOS
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2575628
• 关键词: adrenocorticotropic hormone; arginine vasopressin; clinical research; corpus luteum; corticotropin releasing factor; cortisol; endometrium; exercise; glucocorticoids; hormone regulation /control mechanism; human genetic material tag; human subject; hypercortisolism; hypothalamic pituitary axis; immunoregulation; inflammation; interleukin 1; interleukin 6; menstrual cycle; mifepristone; multiple sclerosis; ovulation; rheumatoid arthritis; somatostatin; tumor necrosis factor alpha

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. Several immune system products, such as the inflammatory cytokines, tumor necrosis Factor-alpha, interleukin-1, and interleukin-6 activate the hypothalamic-pituitary-adrenal (HPA) axis and through it suppress and restrain the inflammatory/immune response. Interleukin-6 is particularly potent in humans, stimulating not only ACTH and cortisol but also arginine-vasopressin (AVP) secretion. Plasma interleukin-6 is elevated in glucocorticoid deficiency states and after exercise. Elevations of interleukin 6 in infectious, inflammatory, and traumatic states may explain the pathogenesis of the Syndrome of Inappropriate AVP Secretion observed in these states. The glucocorticoid antagonist RU 486 potentiated the inflammatory/immune response to a standard inflammatory stimulus in intact animals, suggesting that endogenous glucocorticoids exert anti-inflammatory/immunosuppressive effects at physiological levels. 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. We have called this "immune" CRH. Glucocorticoids and somatostatin 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, blastocyst implantation, 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 inflammatory 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 of relevance to human arthritis and other autoimmune diseases. Patients with rheumatoid arthritis have defective pituitary-adrenal axis responses to inflammatory stimuli and produce excessive amounts of immune CRH in their inflamed joints. Patients with fibromyalgia have a slight hypofunction of their hypothalamic-pituitary-adrenal axis revealed by CRH testing and measurements of urinary free cortisol excretion. Patients with multiple sclerosis have mild hypercortisolism, which is sustained by chronic hypothalamic AVP rather than CRH hypersecretion. The human CRH gene contains estrogen-responsive elements in its promoter region providing an explanation for the sexual dimorphism in the incidence of autoimmune/inflammatory disease. CRH antagonists may be useful in the treatment of autoimmune/inflammatory diseases. We found elevated levels of AVP in rats prone to arthritis and patients with rheumatoid arthritis. AVP potentiated the inflammatory response of rats, suggesting that this peptide also participates in inflammation.

这个项目的目的是增加我们对 两者内分泌和免疫系统之间的相互作用 实验动物和人类。几种免疫系统产品，如 作为炎性细胞因子，肿瘤坏死因子-α， 白介素1和白介素6激活 下丘脑-垂体-肾上腺(HPA)轴并通过它抑制和 抑制炎症/免疫反应。白介素6尤其是 对人类有效，不仅刺激ACTH和皮质醇，而且还 精氨酸加压素(AVP)分泌。血浆白介素6升高 在糖皮质激素缺乏状态和运动后。的高程 处于感染、炎症和创伤状态的白介素6可能 AVP分泌异常综合征的病机解释 在这些状态下观察到的。糖皮质激素拮抗剂RU 486 增强对标准炎症的炎症/免疫反应 对完整动物的刺激，表明内源性糖皮质激素 在生理状态下发挥抗炎/免疫抑制作用 级别。我们最近证明了促肾上腺皮质激素释放激素 (CRH)是在局部炎症部位产生的，具有深刻的 自分泌/旁分泌水平的促炎作用。我们已经打电话给 这种“免疫的”CRH。糖皮质激素和生长抑素抑制及RU 486 显著增加炎症部位局部免疫CRH的分泌。 免疫CRH在卵巢和子宫内膜中被发现，在那里它可能 参与排卵、黄体溶解等炎症现象， 胚泡着床和月经。RU 486允许 易感大鼠中枢神经系统缺陷的鉴定 关节炎。在这些动物中，糖皮质激素对 应激介质不足以抑制以下免疫系统 煽动性的侮辱。实际缺陷是全局性的，位于 下丘脑CRH神经元的水平，它对所有的 已知的兴奋剂，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 新的和与人类关节炎和其他自身免疫性疾病相关的。 类风湿性关节炎患者存在垂体-肾上腺轴缺陷 对炎性刺激的反应并产生过量的免疫力 炎症关节中的CRH。纤维肌痛患者有轻微的 CRH显示下丘脑-垂体-肾上腺轴功能减退 尿中游离皮质醇排泄量的检测。病人 患有多发性硬化症的人有轻微的皮质醇亢进，这是持续的 通过慢性下丘脑AVP而不是CRH高分泌。人类 CRH基因启动子区域含有雌激素反应元件 提供了一种解释性二型性的发病率 自身免疫性/炎症性疾病。CRH拮抗剂可能在 治疗自身免疫性/炎症性疾病。我们发现了高水平的 AVP在易患关节炎的大鼠和类风湿性关节炎患者中的作用。 AVP增强了大鼠的炎症反应，提示这一点 多肽也参与炎症反应。