title: Signal transduction controls heterogeneous NF-κB dynamics and target gene expression through cytokine-specific refractory states.
abstract: Cells respond dynamically to pulsatile cytokine stimulation. Here we report that single, or well-spaced pulses of TNFα (>100 min apart) give a high probability of NF-κB activation. However, fewer cells respond to shorter pulse intervals (<100 min) suggesting a heterogeneous refractory state. This refractory state is established in the signal transduction network downstream of TNFR and upstream of IKK, and depends on the level of the NF-κB system negative feedback protein A20. If a second pulse within the refractory phase is IL-1β instead of TNFα, all of the cells respond. This suggests a mechanism by which two cytokines can synergistically activate an inflammatory response. Gene expression analyses show strong correlation between the cellular dynamic response and NF-κB-dependent target gene activation. These data suggest that refractory states in the NF-κB system constitute an inherent design motif of the inflammatory response and we suggest that this may avoid harmful homogenous cellular activation.
authors.affiliation: Systems Microscopy Centre, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Antony
authors.initials: A
authors.lastname: Adamson
authors.affiliation: Systems Microscopy Centre, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Boddington
authors.affiliation: Systems Microscopy Centre, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Polly
authors.identifier: 0000-0002-1617-6153
authors.initials: P
authors.lastname: Downton
authors.affiliation: Systems Microscopy Centre, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: William
authors.initials: W
authors.lastname: Rowe
authors.affiliation: Systems Microscopy Centre, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: James
authors.initials: J
authors.lastname: Bagnall
authors.affiliation: Systems Microscopy Centre, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Connie
authors.initials: C
authors.lastname: Lam
authors.affiliation: The Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
authors.forename: Apolinar
authors.initials: A
authors.lastname: Maya-Mendoza
authors.affiliation: Systems Microscopy Centre, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Schmidt
authors.affiliation: Systems Microscopy Centre, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Claire V
authors.initials: CV
authors.lastname: Harper
authors.affiliation: Systems Microscopy Centre, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: David G
authors.initials: DG
authors.lastname: Spiller
authors.affiliation: Warwick Systems Biology and Mathematics Institute, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Rand
authors.affiliation: Systems Microscopy Centre, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Dean A
authors.initials: DA
authors.lastname: Jackson
authors.affiliation: Systems Microscopy Centre, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Michael R H
authors.initials: MR
authors.lastname: White
authors.affiliation: Systems Microscopy Centre, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Pawel
authors.identifier: 0000-0002-0363-0716
authors.initials: P
authors.lastname: Paszek
mesh_terms: D045744:Cell Line, Tumor; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000494:pharmacology*; D008164:Luminescent Proteins / Q000235:genetics / Q000276:immunology; D000072000:NF-KappaB Inhibitor alpha / Q000235:genetics* / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics* / Q000276:immunology; D009474:Neurons; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics* / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000097573:Red Fluorescent Protein
chemical_list: D049452:Green Fluorescent Proteins; D051550:I-kappa B Kinase; D053583:Interleukin-1beta; D008164:Luminescent Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D034741:RNA, Small Interfering; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha; D000097573:Red Fluorescent Protein; C508585:IL1B protein, human; C485184:enhanced green fluorescent protein; C076529:TNFAIP3 protein, human