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Delayed Resolution of Acute Inflammation in Ulcerative Colitis Is Associated with Elevated Cytokine Release Downstream of TLR4

Rahman, FZ; Smith, AM; Hayee, B; Marks, DJB; Bloom, SL; Segal, AW; (2010) Delayed Resolution of Acute Inflammation in Ulcerative Colitis Is Associated with Elevated Cytokine Release Downstream of TLR4. PLOS ONE , 5 (3) , Article e9891. 10.1371/journal.pone.0009891. Green open access

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Abstract

Background: Ulcerative colitis (UC) is widely viewed as a leukocyte-mediated disorder. Although strong evidence implicates an exuberant response to microbial components in its pathogenesis, no intrinsic immune defect has been identified and the underlying pathogenic mechanisms remain obscure.Methodology/Principal Findings: The acute immune response to bacterial injection was determined in UC patients with quiescent disease and directly compared to healthy control subjects. Monocyte-derived macrophages were used to investigate bacterial recognition mechanisms in vitro. An exuberant and protracted acute inflammatory response to bacteria was evident in patients with UC, which coincides with increased systemic levels of CXCL10. Macrophages stimulated with bacteria and Toll-like receptor (TLR) ligands revealed a specific defect in the TLR4 response in UC. The defect resulted in the over-expression of a number of pro-inflammatory molecules under transcriptional control of the adaptor TIR-domain containing adaptor inducing interferon-b (TRIF).Conclusion: These findings highlight a dysregulated innate immune response with over-expression of molecules associated with leukocyte recruitment and activation that may eventuate in the hallmark chronic immune-mediated inflammation of UC.

Type: Article
Title: Delayed Resolution of Acute Inflammation in Ulcerative Colitis Is Associated with Elevated Cytokine Release Downstream of TLR4
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0009891
Publisher version: http://dx.doi.org/10.1371/journal.pone.0009891
Language: English
Additional information: © 2010 Rahman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This work was supported by The Wellcome Trust (GHACB) (www.wellcome.ac.uk) and The Broad Medical Research Program (GHADY) (www.broadmedical.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: CHRONIC HEPATITIS-C, CD4(+) T-CELLS, CROHNS-DISEASE, BOWEL-DISEASE, TRIF, PATHOGENESIS, LOCI, MICE, INTERFERON-BETA-1A, INHIBITION
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Eastman Dental Institute
URI: https://discovery.ucl.ac.uk/id/eprint/76260
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