D. Turner, P. Paszek, D. Woodcock, D. Nelso, C. Horton, Y. Wang, D. Spiller, D. Rand, M. White and C. Harper
Physiological levels of TNFalpha stimulation induce stochastic dynamics of NF-kappaB responses in single living cells.
Journal of Cell BiologyVol. 123 No. 16
(2010) pp. p.p 2834-2843
AbstractNuclear factor kappa B (NF-Ã?ÂºB) signalling is activated by cellular stress and inflammation and regulates cytokine expression. We applied single-cell imaging to investigate dynamic responses to different doses of tumour necrosis factor alpha (TNFÃ?Â±). Lower doses activated fewer cells and those responding showed an increasingly variable delay in the initial NF-Ã?ÂºB nuclear translocation and associated IÃ?ÂºBÃ?Â± degradation. Robust 100 minute nuclear:cytoplasmic NF-Ã?ÂºB oscillations were observed over a wide range of TNFÃ?Â± concentrations. The result is supported by computational analyses, which identified a limit cycle in the system with a stable 100 minute period over a range of stimuli, and indicated no co-operativity in the pathway activation. These results suggest that a stochastic threshold controls functional all-or-nothing responses in individual cells. Deterministic and stochastic models simulated the experimentally observed activation threshold and gave rise to new predictions about the structure of the system and open the way for better mechanistic understanding of physiological TNFÃ?Â± activation of inflammatory responses in cells and tissues.