Institute of Fundamental Technological Research
Polish Academy of Sciences

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Antony Adamson


Recent publications
1.  Downton P., Bagnall James S., England H., Spiller David G., Humphreys Neil E., Jackson Dean A., Paszek P., White Michael R.R., Adamson Antony D., Overexpression of IκB⍺ modulates NF-κB activation of inflammatory target gene expression, Frontiers in Molecular Biosciences, ISSN: 2296-889X, DOI: 10.3389/fmolb.2023.1187187, Vol.10, pp.1187187-1-15, 2023

Abstract:
Cells respond to inflammatory stimuli such as cytokines by activation of the nuclear factor-κB (NF-κB) signalling pathway, resulting in oscillatory translocation of the transcription factor p65 between nucleus and cytoplasm in some cell types. We investigate the relationship between p65 and inhibitor-κB⍺ (IκBα) protein levels and dynamic properties of the system, and how this interaction impacts on the expression of key inflammatory genes. Using bacterial artificial chromosomes, we developed new cell models of IκB⍺-eGFP protein overexpression in a pseudo-native genomic context. We find that cells with high levels of the negative regulator IκBα remain responsive to inflammatory stimuli and maintain dynamics for both p65 and IκBα. In contrast, canonical target gene expression is dramatically reduced by overexpression of IκBα, but can be partially rescued by overexpression of p65. Treatment with leptomycin B to promote nuclear accumulation of IκB⍺ also suppresses canonical target gene expression, suggesting a mechanism in which nuclear IκB⍺ accumulation prevents productive p65 interaction with promoter binding sites. This causes reduced target promoter binding and gene transcription, which we validate by chromatin immunoprecipitation and in primary cells. Overall, we show how inflammatory gene transcription is modulated by the expression levels of both IκB⍺ and p65. This results in an anti-inflammatory effect on transcription, demonstrating a broad mechanism to modulate the strength of inflammatory response.

Keywords:
NF-κB, inflammation, IκB⍺, overexpression, gene expression, localisation

Affiliations:
Downton P. - other affiliation
Bagnall James S. - other affiliation
England H. - other affiliation
Spiller David G. - other affiliation
Humphreys Neil E. - other affiliation
Jackson Dean A. - other affiliation
Paszek P. - IPPT PAN
White Michael R.R. - University of Manchester (GB)
Adamson Antony D. - other affiliation
2.  Bagnall J., Boddington C., England H., Brignall R., Downton P., Alsoufi Z., Boyd J., Rowe W., Bennett A., Walker C., Adamson A., Patel Nisha M. X., O’Cualain R., Schmidt L., Spiller David G., Jackson Dean A., Müller W., Muldoon M., White Michael R. H.R., Paszek P., Quantitative analysis of competitive cytokine signaling predicts tissue thresholds for the propagation of macrophage activation, Science Signaling, ISSN: 1945-0877, DOI: 10.1126/scisignal.aaf3998, Vol.11, No.540, pp.1-15, 2018

Abstract:
Toll-like receptor (TLR) signaling regulates macrophage activation and effector cytokine propagation in the constrained environment of a tissue. In macrophage populations, TLR4 stimulates the dose-dependent transcription of nuclear factor κB (NF-κB) target genes. However, using single-RNA counting, we found that individual cells exhibited a wide range (three orders of magnitude) of expression of the gene encoding the proinflammatory cytokine tumor necrosis factor–α (TNF-α). The TLR4-induced TNFA transcriptional response correlated with the extent of NF-κB signaling in the cells and their size. We compared the rates of TNF-α production and uptake in macrophages and mouse embryonic fibroblasts and generated a mathematical model to explore the heterogeneity in the response of macrophages to TLR4 stimulation and the propagation of the TNF-α signal in the tissue. The model predicts that the local propagation of the TLR4-dependent TNF-α response and cellular NF-κB signaling are limited to small distances of a few cell diameters between neighboring tissue-resident macrophages. In our predictive model, TNF-α propagation was constrained by competitive uptake of TNF-α from the environment, rather than by heterogeneous production of the cytokine. We propose that the highly constrained architecture of tissues enables effective localized propagation of inflammatory cues while avoiding out-of-context responses at longer distances.

Affiliations:
Bagnall J. - other affiliation
Boddington C. - other affiliation
England H. - other affiliation
Brignall R. - other affiliation
Downton P. - other affiliation
Alsoufi Z. - other affiliation
Boyd J. - other affiliation
Rowe W. - other affiliation
Bennett A. - other affiliation
Walker C. - other affiliation
Adamson A. - other affiliation
Patel Nisha M. X. - other affiliation
O’Cualain R. - other affiliation
Schmidt L. - other affiliation
Spiller David G. - other affiliation
Jackson Dean A. - other affiliation
Müller W. - other affiliation
Muldoon M. - other affiliation
White Michael R. H.R. - University of Manchester (GB)
Paszek P. - other affiliation
3.  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:
Adamson A. - other affiliation
Boddington C. - other affiliation
Downton P. - other affiliation
Rowe W. - other affiliation
Bagnall J. - other affiliation
Lam C. - other affiliation
Maya-Mendoza A. - other affiliation
Schmidt L. - other affiliation
Harper Claire V.V. - University of Manchester (GB)
Spiller David G. - other affiliation
Rand David A.A. - University of Warwick (GB)
Jackson Dean A. - other affiliation
White Michael R. H.R. - University of Manchester (GB)
Paszek P. - other affiliation
4.  Ankers John M., Awais R., Jones Nicholas A., Boyd J., Ryan S., Adamson Antony D., Harper Claire V.V., Bridge L., Spiller David G., Jackson Dean A., Paszek P., Sée V., White Michael R.R., Dynamic NF-κB and E2F interactions control the priority and timing of inflammatory signalling and cell proliferation, eLife, ISSN: 2050-084X, DOI: 10.7554/eLife.10473, Vol.5, pp.e10473-1-35, 2016

Abstract:
Dynamic cellular systems reprogram gene expression to ensure appropriate cellular fate responses to specific extracellular cues. Here we demonstrate that the dynamics of Nuclear Factor kappa B (NF-κB) signalling and the cell cycle are prioritised differently depending on the timing of an inflammatory signal. Using iterative experimental and computational analyses, we show physical and functional interactions between NF-κB and the E2 Factor 1 (E2F-1) and E2 Factor 4 (E2F-4) cell cycle regulators. These interactions modulate the NF-κB response. In S-phase, the NF-κB response was delayed or repressed, while cell cycle progression was unimpeded. By contrast, activation of NF-κB at the G1/S boundary resulted in a longer cell cycle and more synchronous initial NF-κB responses between cells. These data identify new mechanisms by which the cellular response to stress is differentially controlled at different stages of the cell cycle.

Affiliations:
Ankers John M. - other affiliation
Awais R. - other affiliation
Jones Nicholas A. - Massachusetts Institute of Technology (US)
Boyd J. - other affiliation
Ryan S. - other affiliation
Adamson Antony D. - other affiliation
Harper Claire V.V. - University of Manchester (GB)
Bridge L. - other affiliation
Spiller David G. - other affiliation
Jackson Dean A. - other affiliation
Paszek P. - other affiliation
Sée V. - other affiliation
White Michael R.R. - University of Manchester (GB)

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