Endocrine-immune-reproductive System Interactions

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的理解，在三个层面，培养细胞，实验动物和人类。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，并刺激单核巨噬细胞分泌IL-10，导致从Thelper-1定向免疫转向thelper -2定向免疫。这些激素还影响新发现的t细胞谱系Thelper17和thelperregg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，一些免疫系统产物，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症免疫反应。微灌注原位检测的人脂肪不仅产生瘦素，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，并因内脏肥胖而进一步升高。我们最近发现两种小分子IL-6拮抗剂和ppar - δ激动剂通过抑制STAT3具有很强的抗炎活性。前一种化合物TB-2-081与IL-6型受体的gp130亚基相互作用，不仅阻断IL-6的活性，还阻断LIF、Oncostatin M和IL-11的活性。细胞的主要变化是STAT3转录因子酪氨酸磷酸化的抑制。后一种化合物GW50516可抑制肝细胞产生几种急性期反应物，因此具有重要的抗炎活性。这种效应也可以通过抑制STAT3在应答基因启动子上的活性来介导。

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. 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. Viruses, including the human immunodeficiency syndrome type-1 (HIV-1), cytomegalovirus (CMV), and Newcastle disease virus (NDV), 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 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. Importantly, these viruses stimulate IL-10 expression in the dendritic cells, while glucocorticoids further potentiate such virus-induced expression of this cytokine. Since IL-10 inhibits synthesis of pro-inflammatory cytokines and has ability to suppress antigen presentation by dendtritic cells and monocytes, synergistic activation of IL-10 by glucocorticoids may explain why exposure to stress and subsequent activation of the HPA axis increases susceptibility to viral infection, and possibly, subsequent development of viral-associated disorders, such as asthma atherosclerosis and caners. Extracellular hyperosmolarity or osmotic stress is a major threat for land organisms, and thus strongly stimulates HPA axis through secretion of ariginine vasopression from the hypothalamus/posterior lobe of the pituitary gland. In addition to this systemic response, osmotic stress also activates a cellular signaling cascade called adaptive response to extracellular hyperosmolarity: Extracellular hyperosmolarity induces and activates a Rel-homology domain-containing transcription factor, the nuclear factor of activated T-cells 5 (NFAT5), which subsequently stimulates transcription of osmotic stress-responsive genes and causes intracellular accumulation of small organic osmolytes to maintain isotonicity between the inside and outside of the cells. We recently evaluated an intracellular signaling cascade responsive to osmotic stress in lymphocytes, and found that a Rho-type guanine nucleotide exchange factor (GEF) Brx or AKAP13 is essential for the osmotic stress-stimulated expression of NFAT5, and is a key component of the intracellular signaling cascade transmitting the extracellular hyperosmolarity signal to the nucleus. Osmotic stress-mediated induction of NFAT5 requires the Brx GEF domain and p38 mitogen-activated kinase (MAPK), while Brx in response to osmotic stress attracts through its C-terminal domain the cJun kinase (JNK)-interacting protein (JIP) 4, a scaffold specific to activation of the p38 MAPK cascade and NFAT5, coupling activated Rho-type small G proteins to components of the p38 MAPK signaling pathway. Importantly, this signaling system plays a critical role in the differentiation of lymphocytes in the spleen and stimulates production of TNF-alpha and other cytokines. Osmotic stress-mediated activation of this cellular signaling system may also be an important component in immune dysregulation observed in some pathologic conditions accompanied by plasma hyperosmolarity, such as diabetes mellitus, uremia, dehydration and severe burn all of which are known to develop altered cytokine production and immune-associated symptoms/signs.