An NFkB activity calculator to delineate signaling crosstalk: type I and II interferons enhance NFkB via distinct mechanisms

Nuclear factor kappa B (NF?B) is a transcription factor that controls inflammation and cell survival. In clinical histology, elevated NF?B activity is a hallmark of poor prognosis in inflammatory disease and cancer, and may be the result of a combination of diverse micro-environmental constituents. While previous quantitative studies of NF?B focused on its signaling dynamics in single cells, we address here how multiple stimuli may combine to control tissue level NF?B activity. We present a novel, simplified model of NF?B (SiMoN) that functions as an NF?B activity calculator. We demonstrate its utility by exploring how type I and type II interferons modulate NF?B activity in macrophages. Whereas, type I IFNs potentiate NF?B activity by inhibiting translation of I?Ba and by elevating viral RNA sensor (RIG-I) expression, type II IFN amplifies NF?B activity by increasing the degradation of free I?B through transcriptional induction of proteasomal cap components (PA28). Both cross-regulatory mechanisms amplify NF?B activation in response to weaker (viral) inducers, while responses to stronger (bacterial or cytokine) inducers remain largely unaffected. Our work demonstrates how the NF?B calculator can reveal distinct mechanisms of crosstalk on NF?B activity in interferon-containing microenvironments.