Interferon regulatory factor-1 is required for interferon-gamma-induced MHC class I genes in astrocytes

Recent studies have shown that the role of the transcription factor interferon regulatory factor-1 (IRF-1) in the expression of major histocompatibility complex (MHC) class I molecules is tissue-specific. Our previous studies indicated a role for IRF-1 in expression of MHC class I genes in cultured astrocytes in response to interferon-gamma (IFN-gamma). However, the requirement for IRF-1 in MHC class I expression has not been directly analyzed in neural tissue. To further ascertain the importance of IRF-1 in the induction of MHC class I genes in astrocytes in response to IFN-gamma, we analyzed astrocytes from mice with a targeted disruption of the IRF-1 gene (IRF-1(-/-) mice). As expected, astrocytes from wild type (IRF-1(+/+)) mice showed a coordinate increase in both IRF-1 and MHC class I gene expression in response to IFN-gamma. To the contrary, astrocytes from IRF-1(-/-) mice had greatly reduced MHC class I mRNA expression. MHC class I gene promoter activity in astrocytes was controlled entirely through a single enhancer, the MHC-IRF-E, to which IRF-1 bound in response to IFN-gamma in wild type but not in IRF-1(-/-) mouse astrocytes. In vivo, astrocytes in brains of wild type mice readily responded to IFN-gamma to express MHC class I molecules. This correlated with increased MHC class I mRNA in the brain. In contrast, brains of IRF-1(-/-) mice showed no MHC class I gene induction following exposure to IFN-gamma indicating that all cells in the central nervous system (CNS) including astrocytes with the potential to express MHC class I molecules were dependent on IRF-1. These studies conclusively demonstrate a major role for IRF-1/MHC-IRF-E interactions in controlling MHC class I gene expression in astrocytes in response to IFN-gamma.