ENDOCRINE-IMMUNE INTERACTIONS

内分泌免疫相互作用

• 批准号: 6162433
• 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/6162433
• 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 (IL-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. IL-6 causes profound fatigue and somnolence. Plasma interleukin-6 is elevated in glucocorticoid deficiency states and after exercise. Plasma IL-6 and TNFalpha are also elevated in disorders of excessive daytime sleepiness. Elevations of IL-6 in infectious, inflammatory, and traumatic states may explain the pathogenesis of the Syndrome of Inappropriate AVP Secretion observed in these states. We recently demonstrated that corticotropin-releasing hormone (CRH) is produced localy 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. 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. Immune CRH was found in the ovary and endometrium where it may participate in the inflammatory phenomena of ovulation, luteolysis, blastocyst implantation, and menstuation. 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 multiple sclerosis have mild hypercortisolism, which is sustained by chronic hypothalamic AVP rather than CRH hypersecretion. The human CRH gene contains estrogen-responsive elements it 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 autommune/inflammatory diseases. The stress hormones cortisol and catecholamines suppress interleukin-12 and/or stimulate interleukin-10 in human macrophages, causing a shift of the Thelper type towards humoral immunity. The same effect is observed with histamine and substance P.

这个项目的目的是增加我们对 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 炎性细胞因子，肿瘤坏死因子-α，白细胞介素-1， 和白细胞介素-6（IL-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 白细胞介素-6在人类中特别有效，刺激 不仅包括ACTH和皮质醇，还包括精氨酸加压素（AVP）分泌。 IL-6导致严重疲劳和嗜睡。 血浆白细胞介素-6是 糖皮质激素缺乏状态和运动后升高。 血浆 IL-6和TNF α也在白天过度活动的疾病中升高。 困倦 IL-6在感染性、炎症性和 创伤状态可以解释的综合征的发病机制 在这些状态下观察到AVP分泌不当。 我们最近 表明促肾上腺皮质激素释放激素（CRH）的产生 局部在炎症部位，并具有深刻的促炎作用 在自分泌/旁分泌水平。 我们称之为“免疫”CRH。 糖皮质激素和生长抑素抑制，RU 486显著增强 炎症部位免疫CRH的局部分泌。 CRH是一种有效的 肥大细胞的脱髓鞘，这种现象可以被抑制， 非肽类CRH拮抗剂，对1型受体特异，称为 安他拉明 免疫CRH在卵巢和子宫内膜中被发现， 可能参与排卵，黄体溶解， 胚泡植入和月经。 类风湿 垂体-肾上腺轴对炎症反应有缺陷 刺激，并产生过量的免疫CRH在其发炎 接头. 多发性硬化症患者有轻度皮质醇增多症， 这是由慢性下丘脑AVP而不是CRH维持的 分泌过多 人类CRH基因含有雌激素反应元件 它的启动子区域提供了一个解释性别二型性 自身免疫性/炎症性疾病的发病率。 CRH拮抗剂可 可用于治疗自身免疫性/炎性疾病。 的 应激激素皮质醇和儿茶酚胺抑制白细胞介素-12 和/或刺激人巨噬细胞中的白细胞介素-10，引起白细胞介素-10的转移。 Thelper类型的人对体液免疫的影响 观察到同样的效果 组胺和P物质