| Partner: Connie Lam |
Recent publications
| 1. | Adamson A.♦, Boddington C.♦, Downton P.♦, Rowe W.♦, Bagnall J.♦, Lam C.♦, Maya-Mendoza A.♦, Schmidt L.♦, Harper Claire V.V.♦, Spiller David G.♦, Rand David A.A.♦, Jackson Dean A.♦, White Michael R. H.R.♦, Paszek P.♦, Signal transduction controls heterogeneous NF-κB dynamics and target gene expression through cytokine-specific refractory states, Nature Communications, ISSN: 2041-1723, DOI: 10.1038/ncomms12057, Vol.7, pp.12057-1-14, 2016 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. Affiliations:
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