Interactions among oscillatory pathways in NF-kappa B signaling

Area of Science:

• Systems Biology
• Computational Biology
• Biophysics

Background:

• Sustained tumor necrosis factor alpha (TNF-alpha) stimulation induces oscillations in the nuclear factor kappa B (NF-kappa B) system at single-cell and population levels.
• A core negative feedback loop involving NF-kappa B and I-kappa B-alpha is implicated, with suggestions of coupling to other oscillatory pathways.

Purpose of the Study:

• To analyze the response of the NF-kappa B system to pulsed TNF-alpha stimulation.
• To investigate nonlinear resonance phenomena and alternative feedback mechanisms within the NF-kappa B system using computational modeling.

Main Methods:

• Analysis of single-cell data from pulse-stimulated NF-kappa B systems.
• Extensive numerical simulations using a computational model of the NF-kappa B system.
• Coupling the model to sinusoidal signals of varying frequencies and strengths.

Main Results:

• Cellular responses to pulsed TNF-alpha stimulation show entrainment to the pulsing frequency, particularly at high stimulation intensities.
• Numerical simulations reveal observable nonlinear resonances for weak stimulation.
• Excitation of frequencies beyond the forcing and main NF-kappa B oscillator frequencies, leading to quasiperiodic and chaotic dynamics, was observed via sub- and superharmonic resonance.

Conclusions:

• Entrainment in pulse-stimulated experiments is likely due to high stimulation intensity.
• Resonant interactions between pulsatile forcing and system frequencies may be evident under weak stimulation.
• Nonlinearities in the NF-kappa B feedback oscillator can generate diverse nonlinear interactions even with sinusoidal forcing.