Downregulation of IRF-3 levels by ribozyme modulates the profile of IFNA subtypes expressed in infected human cells.
As an early response to viral infection, cells express a number of cellular genes that play a role in innate immunity, including alpha/beta interferons (IFN). IFN-alpha/beta are encoded by a single IFNB gene and multiple, closely related IFNA genes. The induction of these IFN genes in infected cells occurs at the transcriptional level, and two transcription factors of the IRF family, IRF-3 and IRF-7, were shown to play a role in their activation. While the expression of IRF-3 alone was shown to be sufficient for induction of the IFNB gene, induction of all the IFNA subtypes in human cells required the presence of IRF-7. Since IRF-3 is expressed constitutively in all cells examined, the role of IRF-3 in the induction of IFNA genes has not been clarified. Using ribozyme targeted to IRF-3 mRNA, we found that the downregulation of IRF-3 levels in the infected cells inhibited not only the induction of IFNB gene but also the expression of IFNA genes. Furthermore, downmodulation of IRF-3 levels altered the expression profile of IFNA subtypes induced by viral infection. These studies suggest that the ratio between the relative levels of IRF-3 and IRF-7 is a critical determinant for the induction of the individual IFNA subtypes in infected cells.
Yeow
W S
WS
Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Au
W C
WC
Lowther
W J
WJ
Pitha
P M
PM
D001483:Base Sequence; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D005347:Fibroblasts; D005786:Gene Expression Regulation; D006801:Humans; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D016899:Interferon-beta / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D016337:RNA, Catalytic / Q000378:metabolism*; D018108:Respirovirus / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D014777:Virus Diseases / Q000821:virology
D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016898:Interferon-alpha; D016337:RNA, Catalytic; D014157:Transcription Factors; D016899:Interferon-beta