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.

该项目的目的是增加我们对 两者中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，例如 炎性细胞因子，肿瘤坏死因子-Alpha，白介素1， 白介素-6（IL-6）激活下丘脑 - 垂体 - 肾上腺 （HPA）轴并通过它抑制并约束炎症/免疫 回复。 白介素6在人类中特别有效，刺激 不仅是ACTH和皮质醇，还可以分泌精氨酸 - 抗皮蛋白（AVP）。 IL-6会引起深刻的疲劳和哀鸣。 血浆白介素6是 糖皮质激素缺乏状态和运动后升高。 等离子体 IL-6和TNFALPHA的白天疾病也升高 嗜睡。 感染性，炎症性和 创伤状态可以解释综合征的发病机理 在这些州观察到的不当AVP分泌。 我们最近 证明产生了皮质激素释放激素（CRH） 炎症部位的局部人物，具有深远的促炎作用 在自分泌/旁分泌水平上。 我们称这种“免疫” CRH。 糖皮质激素和生长抑素抑制，RU 486显着增强 在炎症部位的局部分泌免疫CRH。 CRH是有效的 肥大细胞的脱粒剂，这种现象可以被A抑制 非肽CRH拮抗剂，针对称为1型受体的特定于 安塔拉姆。 在卵巢和子宫内膜中发现了免疫CRH 可能参与排卵，黄体溶解的炎症现象 胚泡植入和Menstuation。 类风湿的患者 关节炎的垂体 - 肾上腺轴对炎症的反应不良 刺激并在发炎中产生过多的免疫CRH 关节。 多发性硬化症患者患有轻度皮质醇， 由慢性下丘脑AVP而不是CRH持续 大量分泌。 人CRH基因包含雌激素响应元件 它的发起人区域为性二态性提供了解释 在自身免疫/炎症性疾病的发生率中。 CRH拮抗剂可能 在治疗自动疾病/炎症性疾病方面有用。 这 压力激素皮质醇和儿茶酚胺抑制白介素12 和/或在人类巨噬细胞中刺激白介素10，导致转移 轻轻的类型对体液免疫。 观察到相同的效果 与组胺和物质。