Inducing phase-locking and chaos in cellular oscillators by modulating the driving stimuli

Inflammatory responses in eucaryotic cells are often associated with oscillations in the nuclear-cytoplasmic translocation of the transcription factor NF-kB. In most laboratory realizations, the oscillations are triggered by a cytokine stimulus, like the tumor necrosis factor alpha, applied as a step change to a steady level. Here we use a mathematical model to show that an oscillatory external stimulus can synchronize the NF-kB oscillations into states where the ratios of the internal to external frequency are close to rational numbers. We predict a specific response diagram of the TNF-driven NF-kB system which exhibits bands of synchronization known as "Arnold tongues". Our model also suggests that when the amplitude of the external stimulus exceeds a certain threshold there is the possibility of coexistence of multiple different synchronized states and eventually chaotic dynamics of the nuclear NF-kB concentration. This could be used as a way of externally controlling immune response, DNA repair and apoptotic pathways.