NF-κB oscillations and cell-to-cell variability

Oscillations in the transcriptional activator NF-kappa B localized in the nucleus have been observed when a cell is stimulated by an external agent. A negative feedback based on the protein I kappa B whose expression is controlled by NF-kappa B is known to be responsible for these oscillations. We study NF-kappa B oscillations, which have been observed both for cell populations by Hoffmann et al. [2002. The I kappa B-NF-kappa B signaling module: temporal control and selective gene activation. Science 298, 1241-1245] and for single cells by Nelson et al. [2004. Oscillations in NF-kappa B signaling control the dynamics of gene expression. Science 306. 704-708]. In order to study cell-to-cell variability we use Gillespie's algorithm, applied to a simplified version of the model proposed by Hoffmann et al. (2002). We consider the amounts of cellular NF-kappa B and activated IKK as external parameters. When these are fixed. we show that intrinsic fluctuations are small in a model with strong transcription, as is the case of the Hoffmann et al. (2002) model. whether transcription is quadratic or linear in the number of NF-kappa B molecules. Intrinsic fluctuations can however be large when transcription is weak. as we illustrate in a model variant. The effect of extrinsic fluctuations can be significant: cell-to-cell fluctuations of the initial amount of cellular NF-kappa B affect mainly the amplitude of nuclear NF-kappa B oscillations, at least when transcription is linear in the number of NF-kappa B molecules. while fluctuations in the amount of activated IKK affect both their amplitude and period, whatever the mode of transcription. In this case model results are in qualitative agreement with the considerable cell-to-cell variability of NF-kappa B oscillations observed by Nelson et al. (2004). (c) 2005 Elsevier Ltd. All rights reserved.