Abstract
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.
Highlights
NFκB is the primary transcriptional regulator of inflammation [1], controlling the expression of inflammatory cytokines and chemokines that activate and coordinate both local and systemic immune responses, as well as tissue remodeling factors that facilitate immune cell invasion and tissue repair [2]
Published mathematical models accurately recapitulate transient NFκB activities and oscillations caused by stimuli such as TNF or LPS [11, 12, 46,47,48] in fibroblasts and a macrophage cell line [49]; these studies focused on a single enzymatic reaction that controls NFκB-activation: the IKK-mediated degradation of NFκB-bound IκB
Conceptualizing an abstracted model, we find that the amount of NFκB that is capable of binding DNA in the nucleus is determined by the abundance of the inhibitory IκB proteins, which in turn is a function of the biochemical reactions governing IκB synthesis and degradation [50]
Summary
NFκB is the primary transcriptional regulator of inflammation [1], controlling the expression of inflammatory cytokines and chemokines that activate and coordinate both local and systemic immune responses, as well as tissue remodeling factors that facilitate immune cell invasion and tissue repair [2]. NFκB controls cell survival genes and its activity is associated with chemoresistance in cancer cells [3]. High NFκB activity in chronic disease is often associated with poor prognosis [4]. Clinical histological screening to inform treatment strategies often involves assessment of NFκB expression or activity [5, 6]. The molecular mechanisms by which the primary NFκB protein RelA is activated in response to inflammatory cytokines or pathogen exposure have been elucidated.
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