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- W4293653669 abstract "ABSTRACT Type I interferons (IFN) induce powerful anti-viral and innate immune responses via the transcription factor, IFN-stimulated gene factor (ISGF3). However, in some pathological contexts type I IFNs are responsible for exacerbating inflammation. Here, we show that a high dose of IFN-β also activates an inflammatory gene expression program in contrast to IFN-λ3, a type III IFN, which elicits only the common anti-viral gene program. We show that the inflammatory gene program depends on a second, potentiated phase in ISGF3 activation. Iterating between mathematical modeling and experimental analysis we show that the ISGF3 activation network may engage a positive feedback loop with its subunits IRF9 and STAT2. This network motif mediates stimulus-specific ISGF3 dynamics that are dependent on ligand, dose, and duration of exposure, and when engaged activates the inflammatory gene expression program. Our results reveal a previously underappreciated dynamical control of the JAK-STAT/IRF signaling network that may produce distinct biological responses, and suggest that studies of type I IFN dysregulation, and in turn therapeutic remedies, may focus on feedback regulators within it. HIGHLIGHTS High dose IFN-β activates a pro-inflammatory gene program in epithelial cells. IFN-β, but not IFN-λ3, induces a second, potentiated phase in ISGF3 activity. ISGF3 induces its subunits to form a stimulus-contingent positive feedback loop. The positive feedback motif is required for the pro-inflammatory gene program." @default.
- W4293653669 created "2022-08-31" @default.
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- W4293653669 date "2022-08-15" @default.
- W4293653669 modified "2023-10-02" @default.
- W4293653669 title "A stimulus-contingent positive feedback loop enables IFN-β dose-dependent activation of pro-inflammatory genes" @default.
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- W4293653669 doi "https://doi.org/10.1101/2022.08.11.503561" @default.
- W4293653669 hasPublicationYear "2022" @default.
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