Abstract NF-kappaB Oscillations and Cell-to-Cell Variability

Oscillations in the transcriptional activator NF-·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·B whose expression is controlled by NF-·B is known to be responsible for these oscillations. These oscillations have been observed both for cell populations by Ho®mann et al. and for single cells by Nelson et al. In order to study cell-to-cell variability we use stochastic simulations (Gillespie's algorithm) applied to a simplified version of the model proposed by Ho®mann et al. We consider the amounts of cellular NF-·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 original model. 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: fluctuations in the amount of activated IKK can affect both the amplitude and period of the oscillations in qualitative agreement with the considerable cell-to-cell variability of the oscillations observed by Nelson et al.