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

• Published in: PloS one Vol. 5; no. 3; p. e9891
• Main Authors: Rahman, Farooq Z., Smith, Andrew M., Hayee, Bu'Hussain, Marks, Daniel J. B., Bloom, Stuart L., Segal, Anthony W.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.03.2010; Public Library of Science (PLoS)
• Subjects: Bacteria; Biological response modifiers; Cell activation; Colitis, Ulcerative - pathology; Colon; Comparative analysis; CXCL10 protein; Cytokines; Cytokines - biosynthesis; Disease control; Drug dosages; E coli; Escherichia coli - metabolism; Gastroenterology; Gastroenterology and Hepatology/Inflammatory Bowel Disease; Gene expression; Gene Expression Regulation; Hepatitis; Humans; Immune response; Immune system; Immunology; Immunology/Immune Response; Immunology/Innate Immunity; Inflammation; Inflammation - pathology; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory response; Innate immunity; Interferon; Interferon-beta - metabolism; Leukocytes - metabolism; Macrophages; Macrophages - metabolism; Medicine; Microorganisms; Monocytes; Monocytes - metabolism; Multiple sclerosis; Oligonucleotide Array Sequence Analysis; Overexpression; Pathogenesis; Patients; Proteins; Rodents; Stress response; Studies; TLR4 protein; Toll-Like Receptor 4 - biosynthesis; Toll-like receptors; Toll-Like Receptors - metabolism; Transcription; Transcription, Genetic; Treatment Outcome; Ulcerative colitis; United Kingdom > UK
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0009891

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. 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-beta (TRIF). 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.