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The NF-κB differentiator circuit
Cytokine concentrations fluctuate in a dynamic manner. Son et al. found that the activity of the NF-κB signaling pathway correlated with the rate of change in the concentrations of the cytokines TNF and IL-1β rather than with absolute cytokine concentrations. This behavior, which corresponds to a differentiator circuit in engineering systems, required negative feedback provided by the regulatory proteins A20 and IκBα to encode cellular memory about prior exposures and enabled distinct transcriptional responses to different patterns of cytokine dynamics. Thus, the behavior of the NF-κB pathway as a differentiator circuit ensures the generation of appropriate responses to complex variations in cytokine concentration dynamics.
Abstract
Cells receive a wide range of dynamic signaling inputs during immune regulation, but how gene regulatory networks measure such dynamic inputs is not well understood. Here, we used microfluidic single-cell analysis and mathematical modeling to study how the NF-κB pathway responds to immune inputs that vary over time such as increasing, decreasing, or fluctuating cytokine signals. We found that NF-κB activity responded to the absolute difference in cytokine concentration and not to the concentration itself. Our analyses revealed that negative feedback by the regulatory proteins A20 and IκBα enabled differential responses to changes in cytokine dose by providing a short-term memory of previous cytokine concentrations and by continuously resetting kinase cycling and receptor abundance. Investigation of NF-κB target gene expression showed that cells exhibited distinct transcriptional responses under different dynamic cytokine profiles. Our results demonstrate how cells use simple network motifs and transcription factor dynamics to efficiently extract information from complex signaling environments.
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