Quantitative characterization and analysis of the dynamic NF-kappaB response in microglia

Background:
Activation of the NF-kappaB transcription factor and its associated gene expression in microglia is a key component in the response to brain injury. Its activation is dynamic and is part of a network of biochemical species with multiple feedback regulatory mechanisms. Mathematical modeling, which has been instrumental for understanding the NF-kappaB response in other cell types, offers a valuable tool to investigate the regulation of NF-kappaB activation in microglia at a systems level.
Results:
We quantify the dynamic response of NF-kappaB activation and activation of the upstream kinase IKK using ELISA measurements of a microglial cell line following treatment with the pro-inflammatory cytokine TNFalpha. A new mathematical model is developed based on these data sets using a modular procedure that exploits the feedback structure of the network. We show that the new model requires previously unmodeled dynamics involved in the stimulus-induced degradation of the inhibitor IkappaBalpha in order to properly describe microglial NF-kappaB activation in a statistically consistent manner. This suggests a more prominent role for the ubiquitin-proteasome system in regulating the activation of NF-kappaB to inflammatory stimuli. We also find that the introduction of nonlinearities in the kinetics of IKK activation and inactivation is essential for proper characterization of transient IKK activity and corresponds to known biological mechanisms. Numerical analyses of the model highlight key regulators of the microglial NF-kappaB response, as well as those governing IKK activation. Results illustrate the dynamic regulatory mechanisms and the robust yet fragile nature of the negative feedback regulated network.
Conclusions:
We have developed a new mathematical model that incorporates previously unmodeled dynamics to characterize the dynamic response of the NF-kappaB signaling network in microglia. This model is the first of its kind for microglia and provides a tool for the quantitative, systems level study the dynamic cellular response to inflammatory stimuli.

Source: http://www.biomedcentral.com/1471-2105/12/276

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