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。这种病毒蛋白可以在艾滋病患者的血清中发现，并通过穿透细胞膜改变未被HIV-1病毒感染的细胞（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Vpr对ppar - β / δ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，并刺激了线粒体的β -氧化和氧气消耗。这些结果表明，Vpr有助于在hiv -1感染患者中经常观察到的能量代谢受损和能量消耗增加。

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.