Endocrine-immune-reproductive System Interactions

内分泌-免疫-生殖系统相互作用

• 批准号: 7968513
• 负责人: Tomoshige Kino
• 金额: $ 46.5万
• 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/7968513
• 关键词: AKAP13 gene; Acute-Phase Proteins; Adipose tissue; Agonist; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation; Asthma; Atherosclerosis; Autoimmune Diseases; Burn injury; C-terminal; Catecholamines; Cell Lineage; Cell Nucleus; Cells; Characteristics; Circadian Rhythms; Complex; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Coupling; Cultured Cells; Cytomegalovirus; Cytomegalovirus Infections; Dehydration; Dendritic Cells; Development; Diabetes Mellitus; Disease; EP300 gene; Endocrine; Endocrine system; Endometrium; Estrogen Receptors; Exposure to; Fatty acid glycerol esters; Genes; Genetic Transcription; Glucocorticoids; Guanine Nucleotide Exchange Factors; HIV-1; Hand; Hepatocyte; Hormonal; Hormone Antagonists; Hormone Responsive; Hormones; Human; Hypothalamic structure; Immune; Immune response; Immune system; Immunity; Immunologic Deficiency Syndromes; In Situ; Inflammation; Inflammatory; Insulin Resistance; Interferons; Interleukin-1; Interleukin-10; Interleukin-11; Interleukin-12; Interleukin-6; Interleukins; JNK-activating protein kinase; LIF gene; Leptin; Leukocytes; Lipodystrophy; Luteolysis; Lymphocyte; MAP Kinase Gene; MAPK14 gene; Mediating; Menstruation; Mitogen-Activated Protein Kinase Kinases; Mitogens; Monomeric GTP-Binding Proteins; Muscle; NFAT5 protein; Newcastle disease virus; Nuclear Hormone Receptors; Obesity; Organism; Ovary; Ovulation; PPAR delta; PPAR gamma; Pathogenesis; Pathologic; Plasma; Play; Posterior Pituitary Gland; Predisposition; Production; Proteins; Rattus; Reproductive Medicine; Reproductive system; Rheumatoid Arthritis; Role; STAT3 gene; Seizures; Sheep; Shigella; Signal Transduction; Signs and Symptoms; Site; Sleep; Spleen; Stress; Syndrome; System; T-Lymphocyte; Tissues; Tumor Necrosis Factor-alpha; Tyrosine Phosphorylation; Uremia; Viral; Viral Antigens; Virus; Virus Diseases; Visceral; Visceral pain; antalarmin; autocrine; clinical application; cytokine; extracellular; histone acetyltransferase; human TNF protein; hypothalamic-pituitary-adrenal axis; macrophage; mast cell; monocyte; natural Blastocyst Implantation; oncostatin M; p38 MAPK Signaling Pathway; paracrine; promoter; receptor; response; rho; scaffold; skeletal; small molecule; transcription factor

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.

该项目的目的是提高我们对三个层次的内分泌系统和免疫系统之间相互作用的理解，即培养的细胞，实验动物和人类。应激激素糖皮质激素和儿茶酚胺抑制白介素（IL）-12的分泌，并刺激单核细胞巨噬细胞的IL-10分泌，从而导致从弱-1转向Thelper-1转向Thelper-2导向的免疫。这些激素还会影响新鉴定的T细胞谱系Thelper17和Thelper-Reg的发育和功能，最近证明，这些谱系在自身免疫性疾病的发病机理中起主要作用。另一方面，几种免疫系统产物，例如细胞因子肿瘤坏死因子-Alpha（TNF-Alpha），IL-1和IL-6，可以激活下丘脑 - 垂体 - 肾上腺肾上腺轴，并通过它抑制和约束炎症免疫反应。通过微灌注原位检查的人脂肪不仅会产生瘦素，还会产生TNF-Alpha和IL-6。这些细胞因子的分泌具有由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提高。我们最近表明，两个小分子IL-6拮抗剂和PPAR-delta激动剂具有通过STAT3抑制作用强大的抗炎活性。前者化合物TB-2-081与IL-6型受体的GP130亚基相互作用，不仅阻止了IL-6的活性，而且还阻断了LIF，Oncostatin M和IL-11的活性。细胞的主要变化是抑制STAT3转录因子的酪氨酸磷酸化。后一种化合物GW50516通过肝细胞抑制了几种急性相应物的产生，因此显示出主要的抗炎活性。该作用还通过抑制响应基因启动子的STAT3活性的抑制来介导。 我们早些时候证明，促肾上腺素释放激素（CRH）是在炎症部位局部生产的，并在自分泌/旁分泌水平上具有深刻的促炎作用。 CRH是肥大细胞的有效脱粒剂，这种现象可以被非肽CRH拮抗剂抑制，该现象特异于称为Antalarmin的1型CRH受体。该拮抗剂在类风湿关节炎的动物模型中明显了全身性抗炎作用，并阻止了志贺氏菌相关的癫痫发作和动物模型中的内脏疼痛。在卵巢和子宫内膜中发现了CRH，它参与了排卵，黄体溶解，胚泡植入和月经的炎症现象。 Antalarin阻断了大鼠的胚胎植入和绵羊的劳动，这表明CRH拮抗剂可能在生殖医学中有临床应用。 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.这些影响进一步有助于病毒扩张和发病机理。 确实，我们证明了HIV-1辅助分子VPR抑制PPAR-GAMMA活性在特征性艾滋病相关的脂质营养不良和胰岛素抵抗综合征的发展中起着潜在的重要作用。在树突状细胞中，在病毒抗原的识别和表现中起着核心作用，CMV或NDV感染，也许是HIV-1，在一组核激素受体的表达中引起巨大变化共激活剂，可能会通过这些细胞改变干扰素和其他细胞因子的分泌/产生。 重要的是，这些病毒刺激树突状细胞中的IL-10表达，而糖皮质激素进一步增强了这种病毒诱导的该细胞因子的表达。 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哮喘动脉粥样硬化和罐头。 细胞外高质度或渗透应激是对土地生物的主要威胁，因此通过从垂体下的下丘脑/后叶中分泌Ariginine加压来强烈刺激HPA轴。除了这种全身反应外，渗透压还激活了一种称为对细胞外高质性的适应性反应的细胞信号传导级联：细胞外的高温性诱导并激活一个含有激活T-cell的核能转录因子，激活T-cells 5（NFAT5）的核因子（NFAT5），后者刺激了遗传的遗传因素，并随后刺激了探索的内在构成的渗透性。有机渗透压在细胞内部和外部之间维持同量。我们最近评估了淋巴细胞中对渗透胁迫的细胞内信号级联反应，发现Rho-type鸟嘌呤核苷酸交换因子（GEF）BRX或AKAP13对于NFAT5的渗透应力刺激了NFAT5的表达至关重要，并且是内部信号透射量表的关键组成部分。 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小G蛋白到p38 MAPK信号通路的组件。重要的是，该信号系统在脾淋巴细胞的分化中起着至关重要的作用，并刺激TNF-α和其他细胞因子的产生。该细胞信号系统的渗透应激介导的激活也可能是在某些病理状况下观察到的免疫失调的重要组成部分，伴随血浆高渗透性，例如糖尿病，尿素，尿毒症，脱水和严重燃烧，所有这些都会形成细胞因子的生产和免疫 - 伴随症状/体征。