Endocrine-immune-reproductive System Interactions

内分泌-免疫-生殖系统相互作用

• 批准号: 8149240
• 负责人: Tomoshige Kino
• 金额: $ 45.56万
• 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/8149240
• 关键词: Endocrine; Immune; Reproductive system

We have performed several lines of experiments to examine the interactions between the endocrine and immune systems. First, 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 Th1- to Th2-directed immunity. These hormones also influence development and functions of newly identified T-cell lineages, Th17 and T-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 previously 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 the leukemia inhibitory factor, 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. 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 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 (DCs), 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. We have written one manuscript based on the results obtained in the mRNA expression profiling of nuclear hormone receptors and coregulators, and have recently submitted it to a journal. Since NOR1, one member of NR4A group nuclear receptors, was the most highly regulated NR upon viral infection in DCs, we obtained NOR1 knockout mice from Dr. Conneely, the Baylor collage of medicine, and has examined impact of viral infection to interferon and cytokine production in DCs purified from NOR1 knockout mice. We found that DCs from these mice showed a significant defect in the cytokine response (interferon alpha/beta and interleukine 12) compared to those from wild type mice. We further performed animal studies in which we infected/treated these mice with CMV or the chemical compounds stimulating the toll-like receptors, and found that NOR1 knockout mice showed attenuated immune response to these agents. In the same line of experiments, we found that CMV and NDV stimulated IL-10 expression in DCs, and glucocorticoids further potentiated such virus-induced expression of this cytokine. Since IL-10 inhibits synthesis of pro-inflammatory cytokines and has ability to suppress antigen presentation by DCs 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 previously reported an intracellular signaling cascade responsive to osmotic stress in lymphocytes: The 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. To further elucidate roles of Brx/NFAT5-mediated osmotic stress on the regulation of the immune system, we are now developing mice carrying specific deletion of the brx gene in DCs/monocytes/macrophages using the Cre/LoxP system. We published in this year a landmark review manuscript discussing the adaptive response to extracellular hyperosmolarity and its implications to physiology and pathophysiology.

我们进行了几组实验来检查内分泌系统和免疫系统之间的相互作用。首先，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，刺激单核巨噬细胞分泌IL-10，导致从Th1定向免疫转向Th2定向免疫。这些激素还会影响新发现的 T 细胞谱系 Th17 和 T-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发挥着重要作用。另一方面，多种免疫系统产物，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症反应。免疫反应。通过微灌注原位检查的人体脂肪不仅产生瘦素，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成比例增加，并因内脏肥胖而进一步升高。我们之前表明，两种小分子（IL-6 拮抗剂和 PPAR-δ 激动剂）通过 STAT3 抑制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，还阻断白血病抑制因子、制瘤素 M 和 IL-11 的活性。细胞中的一个主要变化是 STAT3 转录因子的酪氨酸磷酸化受到抑制。后一种化合物，GW50516，抑制肝细胞产生几种急性期反应物，从而显示出主要的抗炎活性。这种效应也是通过抑制响应基因启动子处的 STAT3 活性来介导的。 病毒，包括人类免疫缺陷综合征 1 型 (HIV-1)、巨细胞病毒 (CMV) 和新城疫 (NDV) 病毒，是宿主免疫和内分泌系统的有效激活剂和调节剂，影响宿主组织中的激素作用，例如如白细胞、脂肪组织和骨骼肌。这些作用进一步促进病毒扩张和发病机制。 事实上，我们证明了 HIV-1 辅助分子 Vpr 抑制 PPAR-γ 活性，在与 AIDS 相关的特征性脂肪营养不良和胰岛素抵抗综合征的发展中发挥潜在重要作用。树突状细胞 (DC) 在病毒抗原的识别和呈递中发挥着核心作用，CMV 或 NDV 以及可能还有 HIV-1 的感染会导致一组核激素受体的表达发生巨大变化，包括糖皮质激素和雌激素受体，以及几种转录共调节因子，例如 p300 和 p160 型组蛋白乙酰转移酶共激活因子，可能改变干扰素和其他物质的分泌/产生这些细胞产生细胞因子。 我们根据核激素受体和共调节因子 mRNA 表达谱的结果撰写了一篇手稿，并于最近提交给一家期刊。由于 NOR1（NR4A 组核受体的成员之一）是 DC 中病毒感染后受到最高度调节的 NR，因此我们从贝勒医学院 Conneely 博士获得了 NOR1 敲除小鼠，并检查了病毒感染对干扰素和细胞因子的影响从 NOR1 敲除小鼠纯化的 DC 中产生。我们发现，与野生型小鼠相比，这些小鼠的 DC 在细胞因子反应（干扰素 α/β 和白细胞介素 12）方面表现出显着缺陷。我们进一步进行了动物研究，用 CMV 或刺激 Toll 样受体的化合物感染/治疗这些小鼠，发现 NOR1 敲除小鼠对这些药物的免疫反应减弱。 在同一系列实验中，我们发现 CMV 和 NDV 刺激 DC 中的 IL-10 表达，而糖皮质激素进一步增强了病毒诱导的这种细胞因子的表达。 由于 IL-10 抑制促炎细胞因子的合成，并能够抑制 DC 和单核细胞的抗原呈递，因此糖皮质激素对 IL-10 的协同激活可以解释为什么暴露于压力和随后的 HPA 轴激活会增加对病毒感染的易感性，并可能导致随后出现与病毒相关的疾病，例如哮喘、动脉粥样硬化和癌症。 细胞外高渗透压或渗透压是陆地生物的主要威胁，因此通过下丘脑/垂体后叶分泌精氨酸血管加压来强烈刺激 HPA 轴。除了这种全身反应外，渗透压还会激活细胞信号级联，称为对细胞外高渗性的适应性反应：细胞外高渗性诱导并激活含有 Rel 同源结构域的转录因子，即活化 T 细胞 5 (NFAT5) 的核因子，随后刺激渗透应激反应基因的转录，并导致细胞内小有机渗透剂的积累，以维持细胞内外的等渗性。我们之前报道了淋巴细胞中对渗透压有反应的细胞内信号级联：Rho 型鸟嘌呤核苷酸交换因子 (GEF) Brx 或 AKAP13 对于渗透压刺激的 NFAT5 表达至关重要，并且是细胞内信号级联的关键组成部分将细胞外高渗信号传递至细胞核。渗透应激介导的 NFAT5 诱导需要 Brx GEF 结构域和 p38 丝裂原激活激酶 (MAPK)，而响应渗透应激的 Brx 通过其 C 末端结构域吸引 cJun 激酶 (JNK) 相互作用蛋白 (JIP) 4，一种特异性激活 p38 MAPK 级联和 NFAT5 的支架，将激活的 Rho 型小 G 蛋白与 p38 MAPK 信号通路的成分偶联。重要的是，该信号系统在脾脏淋巴细胞的分化中发挥着关键作用，并刺激 TNF-α 和其他细胞因子的产生。渗透压介导的细胞信号系统激活也可能是免疫失调的重要组成部分，在一些伴有血浆高渗透压的病理状况下观察到，例如糖尿病、尿毒症、脱水和严重烧伤，所有这些都会导致细胞因子产生改变和免疫相关症状/体征。为了进一步阐明 Brx/NFAT5 介导的渗透压对免疫系统调节的作用，我们现在正在使用 Cre/LoxP 系统开发在 DC/单核细胞/巨噬细胞中携带 brx 基因特异性缺失的小鼠。我们今年发表了一篇具有里程碑意义的综述手稿，讨论了对细胞外高渗透压的适应性反应及其对生理学和病理生理学的影响。