Abstract
The NF-κB pathway is known to transmit merely 1 bit of information about stimulus level. We combined experimentation with mathematical modeling to elucidate how information about TNF concentration is turned into a binary decision. Using Kolmogorov-Smirnov distance, we quantified the cell’s ability to discern 8 TNF concentrations at each step of the NF-κB pathway, to find that input discernibility decreases as signal propagates along the pathway. Discernibility of low TNF concentrations is restricted by noise at the TNF receptor level, whereas discernibility of high TNF concentrations it is restricted by saturation/depletion of downstream signaling components. Consequently, signal discernibility is highest between 0.03 and 1 ng/ml TNF. Simultaneous exposure to TNF or LPS and a translation inhibitor, cycloheximide, leads to prolonged NF-κB activation and a marked increase of transcript levels of NF-κB inhibitors, IκBα and A20. The impact of cycloheximide becomes apparent after the first peak of nuclear NF-κB translocation, meaning that the NF-κB network not only relays 1 bit of information to coordinate the all-or-nothing expression of early genes, but also over a longer time course integrates information about other stimuli. The NF-κB system should be thus perceived as a feedback-controlled decision-making module rather than a simple information transmission channel.
Highlights
Cell signaling is performed by pathways and networks
As the first NF-κB pulse is very similar for both tonic and pulsed TNF stimulation, the value obtained by Cheong et al.[1] for tonic stimulation can be considered as an appropriate estimate of the number of bits transmitted in a single pulse: they found that the NF-κB response can yield at most 0.92 ± 0.01 bit of information
We examine the NF-κB network and, following our earlier study[13], we take into account only the variability in the levels of TNF receptor (TNFR) and NF-κB
Summary
Cell signaling is performed by pathways and networks. The pathways, conceptualized as linear compositions of biochemical signal transduction elements, can be perceived as communication channels that transmit information from stimuli to respective outputs[1]. We should notice that since our analysis is based on sampled one-dimensional probability distributions, we quantify how much information on average is transmitted by a single cell in which NF-κB response is measured at a single time point.
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