Endocrine-immune-reproductive System Interactions

该项目的目的是增加我们对内分泌和免疫系统在培养细胞、实验动物和人类三个层面上相互作用的理解。应激激素糖皮质激素和儿茶酚胺抑制白细胞介素（IL）-12的分泌并刺激单核细胞巨噬细胞分泌IL-10，导致从Thelper-1向Thelper-2定向免疫的转变。这些激素还影响新鉴定的T细胞谱系Thelper 17和Thelper-reg的发育和功能，其中前者最近被证明在自身免疫性疾病的发病机制中起主要作用。另一方面，几种免疫系统产物，如细胞因子肿瘤坏死因子-α（TNF-α）、IL-1和IL-6，激活下丘脑-垂体-肾上腺轴，并通过它抑制和抑制炎性免疫应答。通过微灌注原位检测的人类脂肪不仅产生瘦素，还产生TNF-α和IL-6。这些细胞因子的分泌具有受睡眠影响的昼夜节律，而它们的循环水平与BMI成比例地增加，并通过内脏肥胖进一步升高。 抑郁症、特发性失眠和睡眠呼吸暂停患者的IL-6浓度升高。Enbrel是一种抗TNF-α生物制剂，可降低IL-6浓度，改善睡眠呼吸暂停指数并减少嗜睡。在抑郁症中，IL-6的昼夜节律是颠倒的，早上的水平最高，与这些患者的影响密切相关。睡眠剥夺导致表现下降和疲劳增加，与血浆IL-6浓度升高相关。午睡降低IL-6并提高性能。我们最近发现两种小分子IL-6拮抗剂和PPAR-delta激动剂通过抑制STAT 3具有强的抗炎活性。前一种化合物TB-2-081与IL-6型受体的gp 130亚基相互作用，不仅阻断IL-6的活性，而且阻断LIF、Oncostatin M和IL-11的活性。细胞中的一个主要变化是抑制了STAT 3转录因子的酪氨酸磷酸化。后一种化合物GW 50516抑制肝细胞产生几种急性期反应物，因此显示出主要的抗炎活性。这种效应也通过抑制应答基因启动子处的STAT 3活性来介导。我们先前已经证明促肾上腺皮质激素释放激素（CRH）是在炎症部位局部产生的，并在自分泌/旁分泌水平上具有深刻的促炎作用。CRH是一种有效的肥大细胞去增殖作用，这种现象可以被一种非肽CRH拮抗剂抑制，这种拮抗剂对1型CRH受体有特异性，称为antalarmin。该拮抗剂在类风湿性关节炎的动物模型中具有显著的全身抗炎作用，并在动物模型中阻断志贺氏菌相关的癫痫发作和内脏疼痛。CRH存在于卵巢和子宫内膜中，参与排卵、黄体溶解、胚泡着床和月经的炎症现象。Antalarmin阻断大鼠胚胎着床和绵羊分娩，表明CRH拮抗剂可能在生殖医学中具有临床应用。最后，病毒，包括人类免疫缺陷综合征1型（HIV-1）、巨细胞病毒（CMV）和纽卡斯尔病（NDV）病毒，是宿主免疫和内分泌系统的有效激活剂和调节剂，影响宿主组织如白细胞、脂肪组织和骨骼肌中的激素作用。 这些作用进一步促进病毒扩增和发病机制。 事实上，我们最近证明，HIV-1的辅助分子Vpr抑制PPAR-gamma活性发挥潜在的重要作用，在特征性艾滋病相关的脂肪营养不良和胰岛素抵抗综合征的发展。在树突状细胞中，其在病毒抗原的识别和呈递中起核心作用，CMV或NDV以及可能的HIV-1的感染引起一组核激素受体（包括糖皮质激素和雌激素受体）以及几种转录辅助调节因子（如p300和p160型组蛋白乙酰转移酶辅助激活因子）表达的显著变化，可能改变这些细胞分泌/产生干扰素和其它细胞因子。

The purpose of this project is to increase our understanding of the interactions between the endocrine and immune systems at three levels, cultured cells, experimental animals and humans. The stress hormones glucocorticoids and catecholamines inhibit the secretion of Interleukin (IL)-12 and stimulate the secretion of IL-10 by monocytes macrophages, leading to a shift from Thelper-1 to Thelper-2-directed immunity. These hormones also influence development and functions of newly identified T-cell lineages, Thelper17 and Thelper-reg, the former of which was recently shown to play a major role in the pathogenesis of autoimmune disorders. On the other hand, several immune system products, such as the cytokines Tumor Necrosis Factor-alpha (TNF-alpha), IL-1, and IL-6, activate the hypothalamic-pituitary-adrenal axis and through it suppress and restrain the inflammatory immune response. Human fat examined in situ by microperfusion produces not only leptin, but also TNF-alpha and IL-6. The secretion of these cytokines has a circadian rhythm that is influenced by sleep, while their circulating levels increase proportionally to the BMI and are further elevated by visceral adiposity. IL-6 concentrations are elevated in patients with depression, idiopathic insomnia and sleep apnea. Enbrel, an anti-TNF-alpha biological, decreases IL-6 concentrations, improves sleep apnea indices and decreases sleepiness. In depression, the circadian rhythm of IL-6 is inverted with highest levels in the morning, correlating strongly with the affect of these patients. Sleep deprivation results in a fall of performance and an increase in fatigue associated with an elevation of plasma IL-6 concentrations. Napping decreases IL-6 and improves performance. We recently showed that two small molecules an IL-6 antagonist and a PPAR-delta agonist have strong anti-inflammatory activities via STAT3 inhibition. The former compound, TB-2-081, interacted with the gp130 subunit of the IL-6-type receptors and blocked the activity not only of IL-6 but also of LIF, Oncostatin M and IL-11. A major change in the cell was the inhibition of the tyrosine phosphorylation of the STAT3 transcription factor. The latter compound, GW50516, inhibited the production of several acute phase reactants by hepatic cells showing thus major anti-inflammatory activity. This effect was also mediated by inhibition of STAT3 activity at the promoter of responsive genes. We had demonstrated earlier that corticotropin-releasing hormone (CRH) is produced locally at sites of inflammation and has profound pro-inflammatory effects at an autocrine/paracrine level. CRH is a potent degranulator of mast cells, a phenomenon that can be inhibited by a nonpeptide CRH antagonist, specific for type 1 CRH receptors called antalarmin. This antagonist has marked systemic anti-inflammatory actions in an animal model of rheumatoid arthritis, and blocks Shigella -related seizures and visceral pain in animal models. CRH was found in the ovary and endometrium, where it participates in the inflammatory phenomena of ovulation, luteolysis, blastocyst implantation, and menstruation. Antalarmin blocked embryo implantation in rats and labor in sheep, suggesting that CRH antagonists may have clinical applications in reproductive medicine. Finally, viruses, including the human immunodeficiency syndrome type-1 (HIV-1), cytomegalovirus (CMV), and Newcastle disease (NDV) viruses, are potent activators and modulators of the host immune and endocrine systems, influencing hormonal actions in host tissues, such as leukocytes, adipose tissue and skeletal muscles. These effects further contribute to viral expansion and pathogenesis. Indeed, we recently demonstrated that HIV-1 accessory molecule Vpr suppresses PPAR-gamma activity playing a potentially important role in the development of the characteristic AIDS-associated lipodystrophy and insulin-resistance syndrome. In dendritic cells, which play a central role in the recognition and presentation of viral antigens, infection of CMV or NDV and perhaps HIV-1, causes dramatic changes in the expression of a group of nuclear hormone receptors, including the glucocorticoid and estrogen receptors, as well as of several transcriptional co-regulators, such as p300 and p160-type histone acetyltransferase coactivators, possibly altering secretion/production of interferons and other cytokines by these cells.