INTERFERON INDUCIBLE TRANSCRIPTION FACTORS: ROLES IN OCU

干扰素诱导转录因子：在 OCU 中的作用

• 批准号: 6414669
• 负责人: Charles E Egwuagu
• 金额: --
• 依托单位: NATIONAL EYE INSTITUTE
• 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/6414669
• 关键词: eye neoplasms; genetically modified animals; interferon gamma; laboratory mouse; lens disorder; neoplasm /cancer genetics; neoplasm /cancer immunology; neoplasm /cancer remission /regression; neoplastic growth; transcription factor; tumor suppressor proteins

Interferon gamma (IFNg) plays important roles in the regulation of systemic immunity and host mechanisms of tumor surveillance. It is efficacious in treatment of certain neoplastic diseases and its anti-tumor effects is thought to derive from activation of immunological effector cells. Furthermore, INFg-inducible factors (IRF-1 and ICSBP) that are thought to be tumor suppressors are deleted in a number of myelogenic leukemias. In this study, we examined whether IFNg can act directly on tumor cells in vivo to suppress their growth. We generated double transgenic (DT) mice with targeted expression of IFNg and the oncogenic SV40 T-Antigen (TAg) in the lens. The DT mice developed lens tumors in utero. In contrast to the TAg mice, the tumor burden progressively decreased with age, resulting in complete regression of the tumor in adult DT mice. Splenic and lymph node T cells from TAg or DT mice did not proliferate in response to TAg, indicating that both strains are tolerant to the transgene. We also found significant increase in the expression of IRF-1, ICSBP and the pro-apoptotic protein, caspase-1 (ICE). Taken together, our data suggest that tumor regression in these eyes resulted from direct anti-tumor effects of IFNg and that the primary impact of IFNg is on tumor progression and not on tumor initiation. On going studies seek to characterize the underlying mechanism. Particular focus is on the role of pro-apoptotic pathways in elimination of neoplastic lens cells.

干扰素伽玛（IFNG）在调节系统性免疫和肿瘤监测的宿主机制中起着重要作用。它有效地治疗某些肿瘤性疾病，其抗肿瘤作用被认为源自免疫效应细胞的激活。此外，被认为是肿瘤抑制剂的INFG诱导因子（IRF-1和ICSBP）在许多骨髓性白血病中被删除。在这项研究中，我们检查了IFNG是否可以直接对体内肿瘤细胞作用以抑制其生长。我们在镜头中产生了具有IFNG和致癌性SV40 T抗原（TAG）的双转基因（DT）小鼠。 DT小鼠在子宫内发生了晶状体肿瘤。与TAG小鼠相反，肿瘤负担随着年龄的增长而逐渐减少，导致成年DT小鼠的肿瘤完全消退。来自TAG或DT小鼠的脾脏和淋巴结T细胞不会响应TAG而增殖，表明这两种菌株对转基因均耐受。我们还发现IRF-1，ICSBP和丙凋亡蛋白Caspase-1（ICE）的表达显着增加。 综上所述，我们的数据表明，这些眼睛中的肿瘤消退是由于IFNG的直接抗肿瘤作用而产生的，而IFNG的主要影响是对肿瘤进展而不是对肿瘤起始的影响。 在进行研究中，试图表征潜在的机制。特别的重点是促凋亡途径在消除肿瘤透镜细胞中的作用。