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.

我们已经进行了几系列实验，以检查内分泌系统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。已知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。这些作用可能进一步促进病毒的扩增和发病机制。事实上，我们证明，HIV-1辅助蛋白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脂肪营养不良和胰岛素抵抗综合征的发展。这种病毒蛋白可以在AIDS患者的血清中发现，并且通过穿透它们的细胞膜而改变未被HIV-1病毒感染的细胞（例如肝细胞和脂肪细胞）的活性。在本财政年度，我们发表了一篇论文，证明了Vpr对PPAR-beta/delta的影响：Vpr增强了该受体的转录活性，通过上调丙酮酸脱氢酶激酶4的表达，导致丙酮酸脱氢酶复合物的活性降低，并刺激线粒体的β-氧化和氧消耗。这些结果表明，Vpr有助于受损的能量代谢和增加的能量消耗经常观察到的HIV-1感染的患者。 在树突状细胞（DCs）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）以及几种转录共调节因子（包括p300和p160型组蛋白乙酰转移酶共激活因子）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。由于NR 4A组核受体的一个成员NOR 1是DC中病毒感染后最高度调节的NR，我们从Baylor Collage of Medicine的Conneely博士获得了NOR 1敲除小鼠，并检查了病原体感染对从NOR 1敲除小鼠纯化的DC的作用的影响。与野生型小鼠相比，来自这些小鼠的DC在白细胞介素（IL）-12对病毒感染的应答中显示出显著缺陷，而NOR-1通过其DNA应答元件在报告基因测定中刺激IL-12 p40启动子活性。NOR-1基因敲除小鼠表现出对弓形虫感染的IL-12产生的显著减少，弓形虫是一种原生动物，IL-12作为宿主防御的重要成分。我们目前正在研究细胞和动物系统中NOR-1对IL-12产生的分子调控的细节。 在同一系列的实验中，我们发现CMV和NDV刺激DC中的IL-10表达，并且糖皮质激素进一步增强这种病毒诱导的这种细胞因子的表达。由于IL-10抑制促炎性细胞因子的合成，并具有抑制DC和单核细胞的抗原呈递的能力，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应激和随后的HPA轴激活增加了对病毒感染的易感性，并且可能增加了随后的病毒相关疾病如哮喘、动脉粥样硬化和癌症的发展。我们发现，病毒感染激活细胞外信号调节激酶（ERK），有丝分裂原活化蛋白激酶家族的成员，这反过来磷酸化的人GR在丝氨酸位于氨基酸位置211和增强GR的转录活性的IL-10启动子。在本财政年度，我们发表了一份基于这些结果的手稿。