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Tomasz Lipniacki
Department of Mechanics and Physics of Fluids
Institute of Fundamental Technological Research

Stochasticity in Early Immune Response

Living cells may be considered noisy or stochastic biochemical reactors. In eukaryotic cells, in which the number of protein or mRNA molecules is relatively large, the stochastic effects originate primarily in regulation of gene activity. Transcriptional activity of a gene can be initiated by trans-activator molecules binding to the specific regulatory site(s) in the target gene. The stochasticity of activator binding and dissociation is amplified by transcription and translation, since target gene activation results in a burst of mRNAs molecules, and each copy of mRNA then serves as a template for numerous protein molecules. In the present paper, we reformulate our model of the NF-kB regulatory module (Lipniacki et al., 2004. J. Theor. Biol. 228: 195-215) in order to analyze a single cell regulation. Ordinary differential equations, used for description of fast reaction channels of processes involving a large number of molecules, are combined with a stochastic switch to account for activity of genes involved. The stochasticity in gene transcription causes simulated cells to exhibit large variability. Moreover none of them behave like an ”average” cell. Although the average mRNA and protein levels remain constant prior to TNF stimulation, and stabilize following a prolonged TNF stimulation, in any single cell these levels oscillate stochastically in the absence of TNF and keep oscillating under the
prolonged TNF stimulation. However in short period of about 90 minutes, most cells are synchronized by the TNF signal, and exhibit similar kinetics. We hypothesize that this synchronization is crucial for proper activation of early genes controlling inflammation. Our theoretical predictions of single cell kinetics are supported by recent experimental studies of oscillations in NF-kB signaling made on single cells (Nelson et al., 2004 Science 306: 704-708 and
2005, Science 308: 52b).

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