REGULATION OF CYTOKINE EXPRESSION BY HIV

HIV 对细胞因子表达的调节

• 批准号: 5200742
• 负责人: K CLOUSE-STREBEL
• 金额: --
• 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/5200742
• 关键词: AIDS dementia complex; HIV envelope protein gp120; cytokine; endothelin; gene induction /repression; human immunodeficiency virus 1; human tissue; interferon gamma; lipopolysaccharides; macrophage; monocyte; phorbols; tissue /cell culture; vasoconstrictors

Monocytes/macrophages play a critical role in the pathogenesis of human immunodeficiency virus (HIV) infection, both as targets viral replication and as sources of multifunctional cytokines. We have previously reported that the HIV-1 envelope glycoprotein, gp120, stimulates secretion of the potent vasoconstrictive peptide, endothelin-1 (ET-1), from human macrophages in a concentration- dependent manner. We also found that circulating monocytes in HIV-infected individuals express the ET-1 gene, while cells from healthy controls do not, and that cerebral macrophages in patients with HIV-encephalopathy are positive for ET-1. Thus, monocyte derived endothelins appear to be stimulated during HIV infection and their potent vasoactive properties could potentially mediate alterations in the cerebral perfusion pattern associated with AIDS dementia complex. Our recent studies looking at the effect of HIV infection on both constitutive and stimulated production of ET-1 by human macrophages suggest that infection with monocytropic HIV-1 isolates that are not neurotropic neither induces ET-1 nor potentiates its production by a known inducer, such as LPS. This analysis is being expanded to include macrophage tropic HIV isolates that are neurotropic to determine their influence on entry of HIV infected cells into the brain and , thus, their potential role in AIDS dementia. Inasmuch as AIDS is a disease characterized by a general dysregulation of cytokine production, we are also investigating the role of various cytokines in the regulation of ET-1 gene expression. We have found that the cytokine, interferon-gamma (IFN-g), is capable of inducing the expression of ET-1 in human monocytes/ macrophages in a concentration-dependent manner. Expression of the ET-1 gene in response to IFN-g occurs late compared to expression in response to inducers such as PMA, suggesting that induction of another cellular protein may precede the induction of ET-1. Investigations concerning potential mechanisms for the induction of ET-1 by IFN-g suggest a role for tumor necrosis factor alpha (TNF-a). Although TNF-a does not directly induce ET-1, it potentiates ET-1 production mediated by IFN-g. Furthermore, induction of ET-1 protein by IFN-g, but not PMA, can be blocked with soluble receptors for TNF. These findings will be used to investigate the mechanism of induction of ET-1 gene expression mediated by pathologic agents, such as bacterial LPS and the HIV envelope protein.

单核/巨噬细胞在人类肿瘤的发病机制中起关键作用， 免疫缺陷病毒（HIV）感染，作为病毒复制的目标 和作为多功能细胞因子的来源。 之前我们已经报道 HIV-1的包膜糖蛋白gp 120刺激了 内皮素-1（ET-1）是一种有效的血管收缩肽， 以浓度依赖性方式抑制巨噬细胞的增殖。 我们还发现 HIV感染个体的循环单核细胞表达ET-1基因， 而健康对照组的细胞则没有， HIV脑病患者ET-1阳性。 因此，在本发明中， 单核细胞衍生的内皮素似乎在HIV感染期间被刺激 它们强大的血管活性可能会介导 与艾滋病相关的脑灌注模式改变 痴呆综合症 我们最近的研究关注艾滋病毒的影响 感染对人ET-1组成性和刺激性产生影响 巨噬细胞表明，单嗜性HIV-1分离株的感染， 不是亲神经性的，既不诱导ET-1也不增强其产生 通过已知的诱导剂，例如LPS。 这一分析正在扩大到 包括嗜神经性嗜巨噬细胞HIV分离物，以确定 它们对HIV感染细胞进入大脑的影响，因此， 在艾滋病痴呆症中的潜在作用。 由于艾滋病是一种以普遍失调为特征的疾病， 细胞因子的产生，我们也在研究各种细胞因子的作用。 细胞因子对ET-1基因表达的调控。 我们发现 细胞因子干扰素-γ（IFN-g）能够诱导 内皮素-1在人单核/巨噬细胞中的表达 浓度依赖性。 ET-1基因在应答中的表达 与诱导剂如 作为PMA，这表明另一种细胞蛋白的诱导可能先于 ET-1的诱导。 关于潜在机制的调查 IFN-γ诱导ET-1的表达，提示IFN-γ在肿瘤坏死中的作用 因子α（TNF-α）。 虽然TNF-α并不直接诱导ET-1，但它可以诱导ET-1的表达。 增强IFN-γ介导的ET-1产生。 此外，归纳 IFN-γ对ET-1蛋白的抑制作用可被可溶性TNF-α阻断，而PMA则不能。 TNF受体。 这些发现将用于调查 病理性血管紧张素Ⅱ介导的ET-1基因表达的诱导机制 例如细菌LPS和HIV包膜蛋白。