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Science 324 (5924): 242-246

Copyright © 2009 by the American Association for the Advancement of Science

Pulsatile Stimulation Determines Timing and Specificity of NF-{kappa}B-Dependent Transcription

Louise Ashall,1* Caroline A. Horton,1* David E. Nelson,1* Pawel Paszek,1* Claire V. Harper,1 Kate Sillitoe,1 Sheila Ryan,1 David G. Spiller,1 John F. Unitt,2 David S. Broomhead,3 Douglas B. Kell,4 David A. Rand,5 Violaine Sée,1 Michael R. H. White1{dagger}

Abstract: The nuclear factor {kappa}B (NF-{kappa}B) transcription factor regulates cellular stress responses and the immune response to infection. NF-{kappa}B activation results in oscillations in nuclear NF-{kappa}B abundance. To define the function of these oscillations, we treated cells with repeated short pulses of tumor necrosis factor–{alpha} at various intervals to mimic pulsatile inflammatory signals. At all pulse intervals that were analyzed, we observed synchronous cycles of NF-{kappa}B nuclear translocation. Lower frequency stimulations gave repeated full-amplitude translocations, whereas higher frequency pulses gave reduced translocation, indicating a failure to reset. Deterministic and stochastic mathematical models predicted how negative feedback loops regulate both the resetting of the system and cellular heterogeneity. Altering the stimulation intervals gave different patterns of NF-{kappa}B–dependent gene expression, which supports the idea that oscillation frequency has a functional role.

1 Centre for Cell Imaging, School of Biological Sciences, Bioscience Research Building, Crown Street, Liverpool, L69 7ZB, UK.
2 Molecular Biology Department, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK.
3 School of Mathematics, The Alan Turing Building, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
4 Manchester Centre for Integrative Systems Biology, School of Chemistry, and Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess Street, Manchester, M1 7DN.
5 Warwick Systems Biology, Coventry House, University of Warwick, Coventry CV4 7AL, UK.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: mwhite{at}liv.ac.uk

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