Endocrine-immune-reproductive System Interactions

内分泌-免疫-生殖系统相互作用

• 批准号: 8736815
• 负责人: Tomoshige Kino
• 金额: $ 17.47万
• 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/8736815
• 关键词: Acquired Immunodeficiency Syndrome; Adipocytes; Adipose tissue; Amino Acids; Animals; Antigen Presentation; Asthma; Atherosclerosis; Biological Assay; Catecholamines; Cell membrane; Cells; Characteristics; Cultured Cells; Cytomegalovirus; Cytomegalovirus Infections; DNA; Defect; Dehydration; Dendritic Cells; Development; Disease; EP300 gene; Endocrine; Endocrine system; Energy Metabolism; Estrogen Receptors; Exogenous Factors; Exposure to; Family; Functional disorder; Glucocorticoid Receptor; Glucocorticoids; HIV-1; Hepatocyte; Hormonal; Hormones; Host Defense; Human; Immune; Immune system; Immunity; Immunologic Deficiency Syndromes; Infection; Inflammatory; Insulin Resistance; Interferons; Interleukin-10; Interleukin-12; Knockout Mice; Leukocytes; Lipodystrophy; Malignant Neoplasms; Manuscripts; Medicine; Mitochondria; Mitogen-Activated Protein Kinases; Molecular; Mus; Newcastle Disease; Nuclear Hormone Receptors; Nuclear Receptors; Oxygen Consumption; PPAR gamma; PPAR-beta; Pathogenesis; Pathologic; Patients; Play; Positioning Attribute; Predisposition; Production; Protozoa; Publishing; Pyruvate Dehydrogenase Complex; Regulation; Reporter; Reproductive system; Response Elements; Role; Serine; Serum; Side; Skeletal Muscle; Stress; Syndrome; System; Therapeutic; Tissues; Toxoplasmosis; Up-Regulation; Viral; Viral Antigens; Viral Proteins; Virus; Virus Diseases; Wild Type Mouse; base; cytokine; extracellular; histone acetyltransferase; hypothalamic-pituitary-adrenal axis; member; monocyte; pathogen; promoter; pyruvate dehydrogenase kinase 4; receptor; research study; response; vpr Gene Products

We have performed several lines of experiments to examine the interactions between the endocrine and immune systems particularly by focusing on viral infection, including that by the human immunodeficiency syndrome type-1 (HIV-1), cytomegalovirus (CMV) or Newcastle disease (NDV) virus. Viruses are known as 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 may further contribute to viral expansion and pathogenesis. Indeed, we demonstrated that HIV-1 accessory protein Vpr suppresses PPAR-gamma activity playing a potentially important role in the development of the characteristic AIDS-associated lipodystrophy and insulin-resistance syndrome. This viral protein can be found in sera of the AIDS patients and changes activity of the cells uninfected by the HIV-1 virus, such as hepatocytes and adipocytes, by penetrating their cell membrane. In this fiscal year, we published one manuscript that demonstrates the effect of Vpr on the PPAR-beta/delta: Vpr enhanced the transcriptional activity of this receptor, which resulted in reduced activity of the pyruvate dehydrogenase complex through upregulation of the pyruvate dehydrogenase kinase 4 expression, and in stimulation of beta-oxydation and oxygen consumption by mitochondria. These results suggest that Vpr contributes to impaired energy metabolism and increased energy expenditure frequently observed in HIV-1-infected patients. 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, including p300 and p160-type histone acetyltransferase coactivators, possibly altering secretion/production of interferons and other cytokines by these cells. 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 have examined impact of pathogen infection to the action of DCs purified from NOR1 knockout mice. DCs from these mice showed a significant defect in the response of interleukin (IL)-12 to viral infection compared to those from wild type mice, while NOR-1 stimulated the IL-12 p40 promoter activity through its DNA response elements in reporter assays. NOR-1 knockout mice demonstrated significant reduction of IL-12 production against infection of Toxoplasma gondii, a protozoa against which IL-12 acts as an essential component for host defense. We are currently examining details of molecular regulation of NOR-1 on IL-12 production both in the cellular and animal systems. 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 cancers. We found that viral infection activated the extracellular signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase family, which in turn phosphorylated the human GR at serine located at amino acid position 211 and enhanced the transcriptional activity of GR on the IL-10 promoter. In this fiscal year, we published one manuscript based on these results.

我们已经进行了几种实验线，以检查内分泌和免疫系统之间的相互作用，特别是通过关注病毒感染，包括人类免疫缺陷综合征1型（HIV-1），巨细胞病毒（CMV）或纽卡斯尔病（NDV）病毒。病毒被称为宿主免疫和内分泌系统的有效活化剂和调节剂，影响宿主组织中的激素作用，例如白细胞，脂肪组织和骨骼肌。这些影响可能进一步有助于病毒膨胀和发病机理。确实，我们证明了HIV-1辅助蛋白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。该病毒蛋白可以在艾滋病患者的血清中发现，并通过穿透其细胞膜来改变HIV-1病毒未感染的细胞的活性，例如肝细胞和脂肪细胞。 In this fiscal year, we published one manuscript that demonstrates the effect of Vpr on the PPAR-beta/delta: Vpr enhanced the transcriptional activity of this receptor, which resulted in reduced activity of the pyruvate dehydrogenase complex through upregulation of the pyruvate dehydrogenase kinase 4 expression, and in stimulation of beta-oxydation and oxygen consumption by mitochondria.这些结果表明，VPR有助于在HIV-1感染的患者中经常观察到的能量代谢受损和增加的能量消耗。 在树突状细胞（DC）中，在病毒抗原的识别和表现中起着核心作用，CMV或NDV的感染以及HIV-1，以及HIV-1，在一组核激素受体的表达中引起巨大变化，包括糖激素和雌激素受体在内乙酰基转移酶共激活剂，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。由于NR4A组核受体的一位成员NOR1是DC病毒感染时最受高度调节的NR，因此我们从Conneely博士（Baylor的医学拼贴画）中获得了NOR1敲除小鼠，并检查了病原体感染对从NOR1敲除小鼠纯化的DC纯化的作用的影响。与野生型小鼠相比，来自这些小鼠的DC在白介素（IL）-12对病毒感染的反应中存在显着缺陷，而NOR-1通过其在报告基因测定中的DNA响应元件刺激了IL-12 p40启动子活性。 NOR-1敲除小鼠表现出IL-12的产生显着降低，以感染弓形虫Gondii，这是一种原生动物，IL-12是宿主防御的重要组成部分。我们目前正在研究细胞和动物系统中IL-12产生的NOR-1分子调节的细节。 在同一实验线中，我们发现CMV和NDV刺激了DC中的IL-10表达，而糖皮质激素进一步增强了该细胞因子的这种病毒诱导的表达。 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,动脉粥样硬化和癌症。我们发现，病毒感染激活了细胞外信号调节激酶（ERK），这是有丝分裂原激活的蛋白激酶家族的成员，后者又磷酸化了位于氨基酸位置211的丝氨酸的人GR，并增强了IL-10启动子上GR的转录活性。在这个财政年度，我们根据这些结果出版了一份手稿。