Pulsatile stimulation determines timing and specificity of NF-kappaB-dependent transcription.
The nuclear factor kappaB (NF-kappaB) transcription factor regulates cellular stress responses and the immune response to infection. NF-kappaB activation results in oscillations in nuclear NF-kappaB 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-kappaB 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-kappaB-dependent gene expression, which supports the idea that oscillation frequency has a functional role.
Centre for Cell Imaging, School of Biological Sciences, Bioscience Research Building, Crown Street, Liverpool, L69 7ZB, UK.
Louise
L
Ashall
Caroline A
CA
Horton
David E
DE
Nelson
Pawel
P
Paszek
Claire V
CV
Harper
Kate
K
Sillitoe
Sheila
S
Ryan
David G
DG
Spiller
John F
JF
Unitt
David S
DS
Broomhead
Douglas B
DB
Kell
David A
DA
Rand
Violaine
V
Sée
Michael R H
MR
White
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D025461:Feedback, Physiological; D015870:Gene Expression; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D015233:Models, Statistical; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013269:Stochastic Processes; D051996:Transcription Factor RelA / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D011993:Recombinant Fusion Proteins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha