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γ（IFNg）在系统免疫调节和肿瘤监测宿主机制中发挥重要作用。它可有效治疗某些肿瘤疾病，其抗肿瘤作用被认为源自免疫效应细胞的激活。此外，被认为是肿瘤抑制因子的 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 是否可以直接作用于体内肿瘤细胞以抑制其生长。我们培育了双转基因 (DT) 小鼠，其晶状体中靶向表达 IFNg 和致癌 SV40 T 抗原 (TAg)。 DT 小鼠在子宫内出现晶状体肿瘤。与 TAg 小鼠相比，肿瘤负荷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 细胞没有响应 TAg 而增殖，表明这两种品系都对转基因具有耐受性。我们还发现 IRF-1、ICSBP 和促凋亡蛋白 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 IFNg 的直接抗肿瘤作用引起的，并且 IFNg 的主要影响是对肿瘤进展而不是对肿瘤起始的影响。 正在进行的研究旨在描述潜在机制的特征。特别关注促凋亡途径在消除肿瘤性晶状体细胞中的作用。