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

Mitchell, Simon, Mercado, Ellen L, Adelaja, Adewunmi, Ho, Jessica Q, Cheng, Quen J, Ghosh, Gourisankar and Hoffmann, Alexander (2019) An NFkB activity calculator to delineate signaling crosstalk: type I and II interferons enhance NFkB via distinct mechanisms. Frontiers in Immunology, 10 (1425). pp. 1-16. ISSN 1664-3224

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

Item Type: Article
Keywords: mathematical model; signaling crosstalk; interferon; NFκB; systems biology; translational inhibition immunoproteasome / anti-viral response
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
Subjects: R Medicine
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Depositing User: Gemma Hamilton
Date Deposited: 17 Jun 2019 09:45
Last Modified: 21 Aug 2019 14:48

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