Regulation of interferon responses in medulloblastoma cells by interferon regulatory factor-1 and -2

Transcriptional activator interferon regulatory factor (IRF)-1 and repressor IRF-2 are known to play a critical role in the regulation of interferon (IFN) responses and oncogenesis in fibroblasts, Although these two factors are expressed in many tissues, including the brain, the role of IRFs in the central nervous system (CNS) has not been elucidated. We analysed a medulloblastoma cell line, ONS-76, as a CNS-derived model system and generated its derivatives, R1 and R2 cells, which constitutively expressed each mouse IRF-1 and IRF-2 cDNA at high levels. By viral infection, R1 and R2 cells showed IFN-beta gene expression 3 h earlier than the control ONS-76 (C-76) cells, with 2.46- and 2.24-fold increase in IFN-beta production respectively. In the presence of cycloheximide, virally induced IFN-beta gene expression of C-76 cells was suppressed, whereas R1 and R2 cells produced IFN-beta 7.5- and 2.2-fold higher than C-76 cells respectively. On the other hand, induction of IFN-inducible genes was enhanced in R1 cells but was suppressed in R2 cells compared with C-76 cells. These results demonstrate that IRF-1 and IRF-2 may play an important role in the regulation of IFN-beta and IFN-inducible genes and that IRF-2 may have dual functions as an activator and repressor in CNS-derived cells.