ENDOCRINE-IMMUNE INTERACTIONS

内分泌免疫相互作用

• 批准号: 5203308
• 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/5203308
• 关键词: adrenal disorder; adrenocorticotropic hormone; arginine vasopressin; autoimmune disorder; corticotropin releasing factor; cortisol; endocrine pharmacology; fibromyalgia; gender difference; glucocorticoids; hormone regulation /control mechanism; human genetic material tag; human subject; hypothalamic pituitary axis; immunomodulators; immunosuppressive; inflammation; interleukin 6; laboratory rat; mifepristone; multiple sclerosis; pituitary adrenal axis; rheumatoid arthritis; somatostatin; stress

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 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，白细胞介素-β， 1和白细胞介素-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。 血浆白细胞介素-6在糖皮质激素缺乏状态下升高， 锻炼后。 白细胞介素6在感染性，炎症性， 和创伤状态可以解释综合征的发病机制， 在这些状态下观察到AVP分泌不当。 糖皮质激素 拮抗剂RU 486增强了对炎症/免疫应答， 完整动物的标准炎症刺激，表明 内源性糖皮质激素发挥抗炎/免疫抑制作用 生理水平的影响。 我们最近证明， 促肾上腺皮质激素释放激素（CRH）是在局部产生的， 并具有深刻的促炎作用， 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。 免疫CRH是 在卵巢和子宫内膜中发现，在那里它可能参与 排卵、黄体溶解、胚泡着床的炎症现象， 还有月经 RU 486允许识别中枢神经系统 系统缺陷的大鼠易患关节炎。 在这些动物中， 糖皮质激素对应激介质的反应不足以抑制 免疫系统受到炎症损伤。 实际的缺陷是 位于下丘脑CRH神经元水平， 对所有已知的刺激物反应都很差，包括几种细胞因子， 以及血清素乙酰胆碱和去甲肾上腺素 这 病理生理机制是新的，与人类关节炎相关 和其他自身免疫性疾病。 类风湿性关节炎患者有 垂体-肾上腺轴对炎症刺激的反应缺陷， 在发炎的关节中产生过量的免疫CRH。 患有纤维肌痛的患者有轻微的功能减退， CRH试验显示下丘脑-垂体-肾上腺轴， 尿游离皮质醇排泄的测量。 多发性 硬化症有轻度皮质醇增多症，这是持续的慢性 下丘脑AVP而不是CRH分泌过多。 人类CRH基因 在其启动子区含有雌激素反应元件， 对发生率中的两性异形的解释 自身免疫性/炎症性疾病。 CRH拮抗剂可用于治疗 治疗自身免疫性/炎症性疾病。 我们发现 AVP在易患关节炎的大鼠和类风湿关节炎患者中的作用。 AVP增强大鼠的炎症反应，表明这一点 肽也参与炎症。