title: Interactions among oscillatory pathways in NF-kappa B signaling.
abstract: BACKGROUND
  Sustained stimulation with tumour necrosis factor alpha (TNF-alpha) induces substantial oscillations--observed at both the single cell and population levels--in the nuclear factor kappa B (NF-kappa B) system. Although the mechanism has not yet been elucidated fully, a core system has been identified consisting of a negative feedback loop involving NF-kappa B (RelA:p50 hetero-dimer) and its inhibitor I-kappa B-alpha. Many authors have suggested that this core oscillator should couple to other oscillatory pathways.
  
  
  RESULTS
  First we analyse single-cell data from experiments in which the NF-kappa B system is forced by short trains of strong pulses of TNF-alpha. Power spectra of the ratio of nuclear-to-cytoplasmic concentration of NF-kappa B suggest that the cells' responses are entrained by the pulsing frequency. Using a recent model of the NF-kappa B system due to Caroline Horton, we carried out extensive numerical simulations to analyze the response frequencies induced by trains of pulses of TNF-alpha stimulation having a wide range of frequencies and amplitudes. These studies suggest that for sufficiently weak stimulation, various nonlinear resonances should be observable. To explore further the possibility of probing alternative feedback mechanisms, we also coupled the model to sinusoidal signals with a wide range of strengths and frequencies. Our results show that, at least in simulation, frequencies other than those of the forcing and the main NF-kappa B oscillator can be excited via sub- and superharmonic resonance, producing quasiperiodic and even chaotic dynamics.
  
  
  CONCLUSIONS
  Our numerical results suggest that the entrainment phenomena observed in pulse-stimulated experiments is a consequence of the high intensity of the stimulation. Computational studies based on current models suggest that resonant interactions between periodic pulsatile forcing and the system's natural frequencies may become evident for sufficiently weak stimulation. Further simulations suggest that the nonlinearities of the NF-kappa B feedback oscillator mean that even sinusoidally modulated forcing can induce a rich variety of nonlinear interactions.
authors.affiliation: Mathematical Biosciences Institute, The Ohio State University, Jennings Hall, Columbus, Ohio 43210, USA. ywang@mbi.osu.edu
authors.forename: Yunjiao
authors.initials: Y
authors.lastname: Wang
authors.forename: Pawel
authors.initials: P
authors.lastname: Paszek
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Horton
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kell
authors.forename: Michael Rh
authors.initials: MR
authors.lastname: White
authors.forename: David S
authors.initials: DS
authors.lastname: Broomhead
authors.forename: Mark R
authors.initials: MR
authors.lastname: Muldoon
mesh_terms: D001683:Biological Clocks / Q000187:drug effects / Q000502:physiology*; D003198:Computer Simulation; D025461:Feedback, Physiological / Q000502:physiology; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha