Interferon-inducible Transcription Factors: Roles In Ocu

IFNg在宿主免疫中发挥重要作用，在肿瘤和炎症性疾病的治疗中有效。然而，其临床应用受到不良副作用的限制。因此，干扰素生物学研究背后的驱动力之一是确定干扰素反应的组成部分，并利用它们提供干扰素的治疗益处，而不产生相关的副作用。虽然IFNg的大多数临床应用是调节免疫反应，但我们的兴趣是了解其非免疫相关功能。随着人们认识到IFNg的作用是通过干扰素调节因子如IRF-1和ICSBP介导的，确定这些因子是否具有非免疫相关的功能是很有意义的。我们之前通过将SV40 T抗原（TAg）靶向表达到我们的转基因小鼠的无血管晶状体，并在晶状体中组成性激活IRF-1和ICSBP来诱导晶状体瘤变。我们证明了由IRF-1和ICSBP介导的非免疫机制对肿瘤表型的拯救。在本财政年度，我们描述了潜在的机制，并表明它们是通过激活ifng依赖性细胞凋亡和抑制TAg与p53或视网膜母细胞瘤蛋白的相互作用来介导的。我们建立了稳定地共表达TAg和IRF-1和ICSBP的晶状体细胞系，并对这些细胞系进行了分析，发现它们的抗肿瘤作用是通过上调p21、p27、caspase 1的表达和与TAg的结合介导的。综上所述，这些结果表明利用IRF-1和ICSBP的肿瘤抑制活性来提供IFNg的治疗益处而不产生相关的不良反应的潜力。

IFNg plays important roles in host immunity and is efficacious in the treatment of neoplastic and inflammatory diseases. However, its clinical use is limited by undesirable side effects. One of the driving forces behind research on the biology of IFNs has therefore been to define components of the interferon response and exploit them to provide therapeutic benefits of IFN without its associated adverse effects. Although most clinical use of IFNg has been to modulate immunological responses and our interest is in understanding its non-immunity related functions. With the realization that effects of IFNg are mediated through interferon regulatory factors such as IRF-1 and ICSBP, it was of interest to determine whether these factors have non-immunity related function. We had previously induced lens neoplasia by targeting expression of SV40 T Antigen (TAg) to the avascular lens of our transgenic mice with constitutive activation of IRF-1 and ICSBP in the lens. We demonstrated rescue of the neoplastic phenotype by non-immunological mechanisms mediated by IRF-1 and ICSBP. In this fiscal year we characterized the underlying mechanism and show that they are mediated by activation of IFNg-dependent apoptosis and inhibition of TAg interactions either with p53 or retinoblastoma protein. We established lens cells lines stably co-expressing TAg and either IRF-1 and ICSBP and analysis of these lines revealed that their anti-tumor effects are mediated by up-regulating expression of p21, p27, caspase 1 and binding to TAg. Taken together, these results suggest the potential of exploiting the tumor suppressive activities of IRF-1 and ICSBP to provide therapeutic benefits of IFNg without its associated adverse effects.