Regulation of IFN-alpha/beta genes: evidence for a dual function of the transcription factor complex ISGF3 in the production and action of IFN-alpha/beta.
BACKGROUND
Efficient production of interferons (IFNs) in virally infected cells is an essential aspect of the host defence. The transcription factor complex ISGF3 (IFN-stimulated gene factor 3) was originally identified as a critical mediator of the IFN signal; it is formed upon IFN receptor (IFNR) stimulation and binds to ISREs (IFN-stimulated response elements) to activate IFN-inducible genes. It has recently been shown that the DNA binding component of ISGF3, p48 (ISGF3gamma) also binds to virus-inducible elements in the IFN-alpha/beta genes, suggesting a potential new role of p48 in IFN production.


RESULTS
Primary cells from mice with a targeted disruption of the p48 gene show severe defects in virus-induced IFN-alpha/beta gene expression. A similar defect was also observed in cells lacking type I IFNR or Stat1, further demonstrating the role of IFN signalling in the induction of these IFN genes. ISGF3 in fact binds to the virus-inducible elements within the IFN-alpha/beta promoters. We also provide evidence showing that these elements are additionally controlled by an unidentified factor(s) which presumably triggers the primary phase of IFN gene induction.


CONCLUSIONS
Our results demonstrate that the IFN signal transducing complex ISGF3 plays a crucial role in IFN production and suggest that ISGF3 may participate directly in the activation of IFN-alpha/beta promoters. This dual function of ISGF3 may insure the efficient operation of this cytokine system in the host defence.
Harada
H
H
Department of Immunology, Faculty of Medicine, University of Tokyo, Hongo, Japan.
Matsumoto
M
M
Sato
M
M
Kashiwazaki
Y
Y
Kimura
T
T
Kitagawa
M
M
Yokochi
T
T
Tan
R S
RS
Takasugi
T
T
Kadokawa
Y
Y
Schindler
C
C
Schreiber
R D
RD
Noguchi
S
S
Taniguchi
T
T
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004622:Embryo, Mammalian; D005347:Fibroblasts; D005786:Gene Expression Regulation; D007370:Interferon Type I / Q000235:genetics*; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D051379:Mice; D009154:Mutation; D009522:Newcastle disease virus; D011401:Promoter Regions, Genetic; D017471:Receptors, Interferon / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D007370:Interferon Type I; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; C494228:Isgf3g protein, mouse; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors