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Endocrine-immune-reproductive System Interactions

内分泌-免疫-生殖系统相互作用

基本信息

批准号：
8941435
负责人：
Tomoshige Kino
金额：
$ 16.1万
依托单位：
EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
依托单位国家：
美国
项目类别：
财政年份：
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/8941435
关键词：
Acquired Immunodeficiency Syndrome Adipocytes Adipose tissue Amino Acids Animals Antigen Presentation Asthma Atherosclerosis Binding Biological Assay Blood Circulation Catecholamines Cell Cycle Arrest Cell membrane Cells Characteristics Cultured Cells Cytomegalovirus Cytomegalovirus Infections DNA DNA Sequence Defect Dehydration Dendritic Cells Development Disease EP300 gene Endocrine Endocrine system Estrogen Receptors Exogenous Factors Exposure to Family Functional disorder Gene Targeting Genes Glucocorticoid Receptor Glucocorticoids HIV HIV-1 Hepatocyte Hormonal Hormones Host Defense Human Hyperglycemia Hypertriglyceridemia Immune Immune system Immunity Immunologic Deficiency Syndromes Implant Infection Inflammatory Insulin Resistance Interferons Interleukin-10 Interleukin-12 Knockout Mice Leukocytes Lipodystrophy Lipolysis Liver Malignant Neoplasms Manuscripts Medicine Metabolism Mitogen-Activated Protein Kinases Molecular Mus Newcastle Disease Nuclear Hormone Receptors Nuclear Receptors PPAR gamma Pathogenesis Pathologic Patients Peptides Peroxisome Proliferator-Activated Receptors Play Positioning Attribute Predisposition Production Protozoa Publishing Pump Regulation Reporter Reproductive system Response Elements Role Serine Serum Side Skeletal Muscle Stress Syndrome System Therapeutic Tissues Toxoplasmosis Transgenic Mice Viral Viral Antigens Viral Proteins Virus Virus Diseases Wild Type Mouse cytokine extracellular histone acetyltransferase hypothalamic-pituitary-adrenal axis in vivo member monocyte pathogen promoter research study response vpr Gene Products

项目摘要

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 enhances GR transcriptional activity, whereas it suppresses PPAR-gamma and -delta 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 demonstrating impact of Vpr on intermediary metabolism by employing transgenic mice specifically expressing Vpr in adipose tissue and liver, and those implanted with the Alzt pump, which releases a synthetic Vpr peptide into circulation. We found that both mice demonstrated accelerated whole-body lipolysis, hyperglycemia and hypertriglyceridemia. In the liver, they developed severe steatosis with blunted expression of the PPAR-responsive genes and increased expression of GR target genes. Similar to human HIV-infected patients, Vpr circulated in the serum of Vpr-transgenic mice. Vpr blocked differentiation in preadipocytes through cell cycle arrest, whereas in mature adipocytes, it increased lipolysis with reciprocally altered binding of PPARgamma and GR to their recognition DNA sequences in respective target gene promoters. These results thus indicate that Vpr regulates activities of these nuclear receptors in vivo, and most likely, contributes to the development of AIDS-associated lipodystrophy and insulin-resistance syndrome in AIDS 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 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.

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增强GR转录活性，而它抑制PPAR-gamma和-delta活性，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中发挥着潜在的重要作用。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，通过使用在脂肪组织和肝脏中特异性表达Vpr的转基因小鼠以及植入Alzt泵（将合成Vpr肽释放到循环中）的小鼠，证明了Vpr对中间代谢的影响。我们发现，这两种小鼠表现出加速全身脂肪分解，高血糖症和高胆固醇血症。在肝脏中，他们出现了严重的脂肪变性，PPAR反应基因的表达减弱，GR靶基因的表达增加。与人类HIV感染患者相似，Vpr在Vpr转基因小鼠的血清中循环。Vpr通过细胞周期阻滞阻断前脂肪细胞的分化，而在成熟脂肪细胞中，Vpr增加了脂解，并显著改变了PPARgamma和GR与各自靶基因启动子中的识别DNA序列的结合。因此，这些结果表明，Vpr调节这些核受体在体内的活动，最有可能的是，有助于艾滋病相关的脂肪营养不良和胰岛素抵抗综合征在艾滋病患者的发展。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。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Brx mediates the response of lymphocytes to osmotic stress through the activation of NFAT5.

DOI：
10.1126/scisignal.2000081
发表时间：
2009-02-10
期刊：
Science signaling
影响因子：
7.3
作者：
Kino T;Takatori H;Manoli I;Wang Y;Tiulpakov A;Blackman MR;Su YA;Chrousos GP;DeCherney AH;Segars JH
通讯作者：
Segars JH

Virus-induced differential expression of nuclear receptors and coregulators in dendritic cells: implication to interferon production.