A stimulus-contingent positive feedback loop enables IFN-β dose-dependent activation of pro-inflammatory genes

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-{beta} also activates an inflammatory gene expression program in contrast to IFN-{lambda}3, 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. HIGHLIGHTSO_LIHigh dose IFN-{beta} activates a pro-inflammatory gene program in epithelial cells. C_LIO_LIIFN-{beta}, but not IFN-{lambda}3, induces a second, potentiated phase in ISGF3 activity. C_LIO_LIISGF3 induces its subunits to form a stimulus-contingent positive feedback loop. C_LIO_LIThe positive feedback motif is required for the pro-inflammatory gene program. C_LI