title: Interferon regulatory factor-1 is required for interferon-gamma-induced MHC class I genes in astrocytes.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, State University of New York Upstate Medical University, 750 East Adams St., Syracuse, NY 13210, USA. kwj4@cornell.edu
authors.forename: Keith W
authors.initials: KW
authors.lastname: Jarosinski
authors.forename: Paul T
authors.initials: PT
authors.lastname: Massa
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000276:immunology*; D001921:Brain / Q000166:cytology / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000276:immunology; D004742:Enhancer Elements, Genetic / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000276:immunology; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D015533:Transcriptional Activation / Q000187:drug effects / Q000276:immunology
chemical_list: D000998:Antiviral Agents; D004268:DNA-Binding Proteins; D015395:Histocompatibility Antigens Class I; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D016328:NF-kappa B; D010750:Phosphoproteins; D012333:RNA, Messenger; D007371:Interferon-gamma