Endocrine-immune-reproductive System Interactions

我们已经进行了几条实验线来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）或新城疫（NDV）病毒。病毒被认为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）中的激素活动。这些影响可能进一步促进病毒的扩展和发病机制。事实上，我们证明了HIV-1辅助蛋白Vpr抑制ppar - γ和- δ活性，在艾滋病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的重要作用。树突状细胞（dc）在病毒抗原的识别和呈现中起着核心作用，CMV或NDV，也许还有HIV-1的感染会引起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，以及一些转录共调节因子，包括p300和p160型组蛋白乙酰转移酶共激活因子，可能改变这些细胞分泌/产生干扰素和其他细胞因子。由于NOR1是NR4A组核受体的一个成员，是dc病毒感染时最受高度调控的NR，我们从Baylor college of Medicine的Conneely博士那里获得了NOR1敲除小鼠，并研究了病原体感染对从NOR1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对病毒感染的反应中表现出显著缺陷，而在报告基因分析中，NOR-1通过其DNA应答元件刺激IL-12 p40启动子活性。NOR-1敲除小鼠对刚地弓形虫感染的IL-12产生显著降低，而弓形虫是一种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。

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 and -delta 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, 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. Based on these findings, we created one manuscript, which is now under review in a Journal.