In collaborative studies with Dr. Charles Egwuagu (Laboratory of Immunology, NEI) we have been studying the JAK/STAT signaling pathway in the lens. This collaboration resulted in the development of transgenic mice and rats with constitutive expression of gamma interferon in their eyes, which became useful animal models for the study of experimental autoimmune uveitis and anterior uveitis. This ongoing collaboration allowed us to study how constitutive expression of gamma interferon and its induction and activation of gamma interferon-inducible transcription factors in the eye altered the developmental fate of cells destined to become lens fiber cells by altering the pattern of lens gene expression.We found that the expression of the members of the interferon regulatory factors (IRFs) family of transcription factors is not only activated in the gamma interferon transgenic mice, but it is also expressed in the normal lens. Our data indicates that expression of IRF transcription factors is spatially regulated in the lens and that distinct IRFs may contribute to differential gene regulation in the epithelia and fiber compartment of the lens. These findings have important implications for understanding signal transduction pathways in the lens. In another collaborative project with Dr. Charles Egwuagu we generated double transgenic mice expressing gamma interferon (IFN gamma) and the oncogenic SV40 large T antigen (TAg) in the lens. Interferon gamma (IFN gamma) is an anti-neoplastic cytokine used in the treatment of some malignant diseases. However, its use is limited by undesirable side effects resulting from its pleiotropic activities. In this study, we induced lens neoplasia in transgenic mice by targeting expression of SV40 T Antigen (TAg) to the lens and demonstrate complete regression of the tumor by simultaneously expression of IFN gamma in the lens. We show that the neoplastic phenotype is rescued by non-immunological mechanisms mediated by: (I) enhanced expression of IFN gamma-inducible tumor suppressors, IRF-1 and ICSBP; (II) activation of caspase 1, p53 and IFN gamma-dependent apoptosis; (III) inhibition of TAg interactions either with p53 or retinoblastoma protein; (IV) induction of enhanced expression of growth inhibitory proteins, p21WAF1 and p27, by IRF-1 and ICSBP. These results suggest the potential of exploiting the tumor suppressive activities of IRF-1 and ICSBP to provide therapeutic benefits of IFN gamma without its associated adverse effects.
