Papoutsopoulou, Stamatia ORCID: 0000-0001-6665-8508, Burkitt, Michael D ORCID: 0000-0002-5055-6408, Bergey, Francois, England, Hazel, Hough, Rachael, Schmidt, Lorraine, Spiller, David G, White, Michael HR, Paszek, Pawel, Jackson, Dean A et al (show 6 more authors)
(2019)
Macrophage-Specific NF-κB Activation Dynamics Can Segregate Inflammatory Bowel Disease Patients.
FRONTIERS IN IMMUNOLOGY, 10.
2168-.
Other
473700_Papoutsopoulou_Manuscript.DOCX - Author Accepted Manuscript Download (145kB) |
Abstract
The heterogeneous nature of inflammatory bowel disease (IBD) presents challenges, particularly when choosing therapy. Activation of the NF-κB transcription factor is a highly regulated, dynamic event in IBD pathogenesis. Using a lentivirus approach, NF-κB-regulated luciferase was expressed in patient macrophages, isolated from frozen peripheral blood mononuclear cell samples. Following activation, samples could be segregated into three clusters based on the NF-κB-regulated luciferase response. The ulcerative colitis (UC) samples appeared only in the hypo-responsive Cluster 1, and in Cluster 2. Conversely, Crohn's disease (CD) patients appeared in all Clusters with their percentage being higher in the hyper-responsive Cluster 3. A positive correlation was seen between NF-κB-induced luciferase activity and the concentrations of cytokines released into medium from stimulated macrophages, but not with serum or biopsy cytokine levels. Confocal imaging of lentivirally-expressed p65 activation revealed that a higher proportion of macrophages from CD patients responded to endotoxin lipid A compared to controls. In contrast, cells from UC patients exhibited a shorter duration of NF-κB p65 subunit nuclear localization compared to healthy controls, and CD donors. Analysis of macrophage cytokine responses and patient metadata revealed a strong correlation between CD patients who smoked and hyper-activation of p65. These <i>in vitro</i> dynamic assays of NF-κB activation in blood-derived macrophages have the potential to segregate IBD patients into groups with different phenotypes and may therefore help determine response to therapy.
Item Type: | Article |
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Uncontrolled Keywords: | inflammatory bowel disease, NF-kappa B, macrophages, cytokines, Crohn's disease, ulcerative colitis |
Depositing User: | Symplectic Admin |
Date Deposited: | 24 Sep 2019 10:39 |
Last Modified: | 16 Oct 2023 18:01 |
DOI: | 10.3389/fimmu.2019.02168 |
Open Access URL: | https://www.frontiersin.org/articles/10.3389/fimmu... |
Related URLs: | |
URI: | https://livrepository.liverpool.ac.uk/id/eprint/3055744 |