NF-kappaB oscillations and cell-to-cell variability.

Oscillations in the transcriptional activator NF-kappaB localized in the nucleus have been observed when a cell is stimulated by an external agent. A negative feedback based on the protein IkappaB whose expression is controlled by NF-kappaB is known to be responsible for these oscillations. We study NF-kappaB oscillations, which have been observed both for cell populations by Hoffmann et al. [2002. The IkappaB-NF-kappaB signaling module: temporal control and selective gene activation. Science 298, 1241-1245] and for single cells by Nelson et al. [2004. Oscillations in NF-kappaB 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-kappaB 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-kappaB 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-kappaB affect mainly the amplitude of nuclear NF-kappaB oscillations, at least when transcription is linear in the number of NF-kappaB 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-kappaB oscillations observed by Nelson et al. (2004).