Abstract
Nature is governed by local interactions among lower-level sub-units, whether at the cell, organ, organism, or colony level. Adaptive system behaviour emerges via these interactions, which integrate the activity of the sub-units. To understand the system level it is necessary to understand the underlying local interactions. Successful models of local interactions at different levels of biological organisation, including epithelial tissue and ant colonies, have demonstrated the benefits of such ‘agent-based’ modelling [1]–[4]. Here we present an agent-based approach to modelling a crucial biological system – the intracellular NF-κB signalling pathway. The pathway is vital to immune response regulation, and is fundamental to basic survival in a range of species [5]–[7]. Alterations in pathway regulation underlie a variety of diseases, including atherosclerosis and arthritis. Our modelling of individual molecules, receptors and genes provides a more comprehensive outline of regulatory network mechanisms than previously possible with equation-based approaches [8]. The method also permits consideration of structural parameters in pathway regulation; here we predict that inhibition of NF-κB is directly affected by actin filaments of the cytoskeleton sequestering excess inhibitors, therefore regulating steady-state and feedback behaviour.
Highlights
NF-kB is a transcription factor which is central to the regulation of genes involved in inflammatory and immune responses
Activation of NF-kB and its associated pathway of interactions is controlled by inhibitors of NF-kB (IkB) proteins, which sequester the majority of NF-kB in the cytoplasm as complexes by masking their nuclear localisation signals [9]
IkB is phosphorylated by IkB kinases (IKK), causing its destruction [10,11]
Summary
NF-kB is a transcription factor which is central to the regulation of genes involved in inflammatory and immune responses. Activation of NF-kB and its associated pathway of interactions is controlled by inhibitors of NF-kB (IkB) proteins, which sequester the majority of NF-kB in the cytoplasm as complexes by masking their nuclear localisation signals [9]. The newly freed NF-kB is transported into the nucleus, inducing inflammatory genes, including those encoding IkB, regulating the pathway through negative feedback [12,13]. Pathway activation is tightly controlled at multiple levels. Detailed information of the parameters regulating specific steps and their impact on activation is of fundamental importance for understanding the pathway as a whole. Modelling of regulation at the level of the inhibitor has been performed using differential equations, helping to improve understanding of pathway operation and regulation [14,15]. We aim to take a different approach to modelling the pathway in order to gain a different perspective on its operation, with a greater focus on spatial detail and a more direct comparison with experiment
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