Interferon-inducible Transcription Factors: Roles In Ocu

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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.