NF-κB (nuclear factor κB) regulates cellular stress and the immune responses to infection. Its activation results in oscillations in nuclear NF-κB abundance. We treated cells with repeated short pulses of TNFα (tumour necrosis factor α) at various intervals to mimic pulsatile inflammatory signals. At all pulse intervals analysed, we observed synchronous cycles of NF-κB nuclear translocation. Lower frequency stimulations gave repeated full-amplitude translocations, whereas higher frequency pulses gave translocations with reduced amplitude, indicating that the system failed to reset completely. Deterministic and stochastic mathematical models predicted how negative feedback loops might regulate both system resetting and cellular heterogeneity. Altering the stimulation interval gave different patterns of NF-κB-dependent gene expression, supporting a functional role for oscillation frequency. The causes of cell-to-cell variation and the possible functions of these processes in cells and tissues are discussed. The NF-κB system is just one of a number of known biological oscillators that include calcium signalling, transcription cycles, p53, the segmentation clock, the circadian clock, the cell cycle and seasonal rhythms. The way such cycles are integrated could be part of the answer as to how organisms achieve complexity while retaining the robustness of cellular decision-making processes.

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